Persistent ΔFosB expression limits recurrent seizure activity and provides neuroprotection in the dentate gyrus of APP mice

Gabriel S Stephens; Jin Park; Andrew Eagle; Jason You; Manuel Silva-Pérez; Chia-Hsuan Fu; Sumin Choi; Corey P St Romain; Chiho Sugimoto; Shelly A Buffington; Yi Zheng; Mauro Costa-Mattioli; Yin Liu; AJ Robison; Jeannie Chin

doi:10.1016/j.pneurobio.2024.102612

. Author manuscript; available in PMC: 2025 Jun 1.

Published in final edited form as: Prog Neurobiol. 2024 Apr 19;237:102612. doi: 10.1016/j.pneurobio.2024.102612

Persistent ΔFosB expression limits recurrent seizure activity and provides neuroprotection in the dentate gyrus of APP mice

Gabriel S Stephens ^1,^a, Jin Park ¹, Andrew Eagle ², Jason You ^1,^b, Manuel Silva-Pérez ¹, Chia-Hsuan Fu ¹, Sumin Choi ¹, Corey P St Romain ¹, Chiho Sugimoto ², Shelly A Buffington ³, Yi Zheng ¹, Mauro Costa-Mattioli ^1,^c, Yin Liu ⁴, AJ Robison ², Jeannie Chin ^1,^*

PMCID: PMC11406539 NIHMSID: NIHMS2018836 PMID: 38642602

Abstract

Recurrent seizures lead to accumulation of the activity-dependent transcription factor ΔFosB in hippocampal dentate granule cells in both mouse models of epilepsy and mouse models of Alzheimer’s disease (AD), which is also associated with increased incidence of seizures. In patients with AD and related mouse models, the degree of ΔFosB accumulation corresponds with increasing severity of cognitive deficits. We previously found that ΔFosB impairs spatial memory in mice by epigenetically regulating expression of target genes such as calbindin that are involved in synaptic plasticity. However, the suppression of calbindin in conditions of neuronal hyperexcitability has been demonstrated to provide neuroprotection to dentate granule cells, indicating that ΔFosB may act over long timescales to coordinate neuroprotective pathways. To test this hypothesis, we used viral-mediated expression of ΔJunD to interfere with ΔFosB signaling over the course of several months in transgenic mice expressing mutant human amyloid precursor protein (APP), which exhibit spontaneous seizures and develop AD-related neuropathology and cognitive deficits. Our results demonstrate that persistent ΔFosB activity acts through discrete modes of hippocampal target gene regulation to modulate neuronal excitability, limit recurrent seizure activity, and provide neuroprotection to hippocampal dentate granule cells in APP mice.

Keywords: Alzheimer’s disease, epilepsy, neuroprotection, hippocampus, ΔFosB, epigenetic

INTRODUCTION

Alzheimer’s disease (AD) is the most common form of dementia (Scheltens et al., 2021), and is accompanied by neuronal and cognitive deficits that are driven by diverse mechanisms of pathophysiology. A growing literature documents findings that recurrent seizures and epileptiform activity occur in early stages of mild cognitive impairment (MCI) and AD, and have been observed in > 53% of AD patients (Volicer et al., 1995; Amatniek et al., 2006; Vossel et al., 2013; Vossel et al., 2016; Vossel et al., 2017; Lam et al., 2020; Lam and Noebels, 2020; Ranasinghe et al., 2022; Kamondi et al., 2024). These incidence rates may be underestimated due to the relatively infrequent occurrence, primarily non-convulsive phenotypes, propensity to occur during sleep, and anatomical depth of the seizures and epileptiform activity that occur in AD patients, characteristics that make seizure detection difficult (Vossel et al., 2016; Lam et al., 2017; Lam and Noebels, 2020; Lam et al., 2020).

Several AD-related factors may contribute to neuronal hyperexcitability over the course of disease (Harris et al., 2020), Notably, the amyloid beta peptides (Aβ) that accumulate early in AD may play critical roles in the neuronal hyperactivity, epileptiform activity, and seizures that are associated with AD both in human patients as well as in related mouse models of AD neuropathology (Harris et al., 2020; Kamondi et al., 2024). The elevation of Aβ levels is one of the earliest features in AD progression, and predominates the preclinical phase (Jack et al., 2013). Notably, epileptiform activity has also been detected very early in disease progression, and its occurrence has been linked to faster rates of cognitive decline (Vossel et al., 2013; Vossel et al., 2016; Vossel et al., 2017; Kamondi et al., 2024). Individuals that carry AD-linked autosomal dominant mutations that affect Aβ production have high incidence of seizures, and individuals with late onset AD without such mutations also exhibit seizures and epileptiform activity (Amatniek et al., 2006; Vossel et al., 2017; Kamondi et al., 2024).

Accordingly, genetically engineered mouse models of AD neuropathology have been used to study the incidence and consequences of seizures. Spontaneous epileptiform activity has been characterized in a number of transgenic and knock-in mouse lines that express human AD-linked mutations and produce human Aβ, indicating that such hyperexcitability is intimately linked to disease pathogenesis (Palop et al., 2007; Minkeviciene et al., 2009; Chin, 2011; Scharfman, 2012; Born, 2015; Kam et al., 2016; Johnson et al., 2020; Liu et al., 2019; Yao et al., 2023).

Notably, although seizures are relatively infrequent in AD and in related mouse models, they appear to strongly influence cognitive function since anti-seizure medicines reduce epileptiform activity and improve cognition in individuals with MCI or AD, and in related AD mouse models (Sanchez et al., 2012; Bakker et al., 2012; Bakker et al., 2015; Fu et al., 2019; Vossel et al., 2021). This is not surprising given that recurrent seizures and epileptiform activity are associated with cognitive comorbidities in epilepsy and in other conditions associated with seizures, such as Down syndrome, autism spectrum disorders, and other neurodevelopmental disorders such as Rett syndrome (Matsuo et al., 2011; Tarquinio et al., 2017; Altuna et al., 2021; Selvarajah et al., 2021). Indeed, there are many similarities between the neuronal and cognitive profiles of individuals with AD and those with temporal lobe epilepsy (TLE) (Palop and Mucke, 2009; Chin and Scharfman, 2013; Sen et al., 2018; Reyes et al., 2021; Hanke et al., 2022). The molecular mechanisms by which seizures lead to long-lasting effects on various aspects of neuronal and cognitive function have been the subject of extensive research (Holmes, 2015; Chauviere, 2020).

One biological mechanism that can translate even infrequent seizures into long-lasting effects on brain function is epigenetic control of gene expression, which enables persistent (dys)regulation of gene expression. Several modes of epigenetic regulation in epilepsy have been characterized (Roopra et al., 2012; McClelland et al., 2014; Henshall and Kobow, 2015; Bernard, 2016; Kobow and Blumcke, 2018). We have demonstrated that ΔFosB, an activity-dependently expressed transcription factor, plays key roles in epigenetic gene regulation in pilocarpine and kainate models of epilepsy as well as in transgenic amyloid precursor protein (APP) mice used to study AD (Corbett et al., 2017; You et al., 2017; You et al., 2018; Stephens et al., 2020). ΔFosB has a long half-life that results in its accumulation in the nuclei of chronically active neurons (Hope et al., 1994a; Hope et al., 1994b; Chen et al., 1995; Hiroi et al., 1998; Chen et al., 2000; Renthal et al., 2008; Robison and Nestler, 2022). In conditions with recurrent seizures, ΔFosB suppresses expression of the calcium- and plasticity-related genes cFos and calbindin, with negative consequences on hippocampal spatial memory (Corbett et al., 2017; You et al., 2017). Chromatin immunoprecipitation and sequencing (ChIP-seq) studies have demonstrated that in mouse models with recurrent seizures, ΔFosB binds a number of gene targets that regulate various aspects of neuronal function, including neurogenesis, cell stress and immunity, chromatin remodeling, and neuronal excitability (You et al., 2018; Stephens et al., 2020). Thus, the actions of ΔFosB on neuronal function may be widespread and long-lasting. Indeed, analysis of ΔFosB gene targets using Cleavage Under Targets and Release Under Nuclease (CUT&RUN) sequencing also demonstrates that ΔFosB interacts with the chromatin remodeling protein BRG1 (Yeh et al., 2023), which may contribute to ΔFosB’s ability to coordinate gene expression over long periods of time.

Our previous work demonstrated that cFos and calbindin are two gene targets that are epigenetically suppressed by ΔFosB and that mediate, at least in part, the negative effect of ΔFosB on hippocampal memory (Corbett et al., 2017; You et al., 2017). However, the control of expression of both cFos and calbindin have been demonstrated to impart neuroprotective effects in various neurological conditions (Nagerl et al., 2000; Rawat et al., 2016), suggesting that the actions of ΔFosB may serve a neuroprotective role. Indeed, ΔFosB reduces excitability of hippocampal CA1 neurons (Eagle et al., 2018), and seizure-induced ΔFosB may support cellular adaptations to electroconvulsive shock (Chen et al., 1995; Hiroi et al., 1998). Moreover, FosB knockout mice exhibit spontaneous seizure activity (Yutsudo et al., 2013). These findings together suggest that ΔFosB activity in the hippocampus may act over long periods to restrict excitability at the cost of spatial memory. This hypothesis is consistent with previous ChIP-seq studies that identified a number of excitability-related genes as ΔFosB targets in both APP mice and pilocarpine-treated mice with chronic seizures (You et al., 2018; Stephens et al., 2020).

Here, we tested the hypothesis that ΔFosB acts over long periods of time to restrict neuronal excitability and maintain neuroprotection in APP mice, using viral-mediated expression of ΔJunD to interfere with ΔFosB signaling over the course of several months. Our results demonstrate that persistent ΔFosB activity can act through discrete modes of hippocampal target gene regulation, which can either stabilize or alter gene expression, to restrict recurrent seizure activity and provide neuroprotection to hippocampal dentate granule cells (DGCs) in APP mice.

MATERIALS AND METHODS

Mice.

We used heterozygous transgenic mice that express human amyloid precursor protein (APP) carrying both the Swedish (K670N, M671L) and Indiana (V717F) mutations driven by the platelet-derived growth factor beta chain (PDGF-β) promoter (Line J20; hAPP770 numbering) (Mucke et al., 2000). This J20 line was backcrossed for over 10 generations onto a C57BL/6 background, maintaining heterozygosity through breeding with wild-type C57BL/6 mice from The Jackson Laboratory. Littermate controls consisted of age- and sex-matched non-transgenic (NTG) mice. Mice were maintained on a 12:12 light/dark cycle in cages with pelleted cellulose bedding and EnviroPak nesting material, and ad libitum access to water and LabDiet 5V5R chow. Mice were group-housed 4–5/cage until appropriate ages for experimental studies, after which they were singly-housed in a quiet environment for 2 days prior to experimentation and/or sacrifice for brain extraction. APP and NTG mice were studied between the ages of 2 to 5.5-months old, depending on length of viral expression, corresponding to early phases of disease progression. These APP mice exhibit epileptiform spikes beginning around 1 month of age, seizures around 2 months of age, cognitive deficits that are robust by 3–4 months of age, and formation of Aβ plaques around 6 months of age (Mucke et al., 2000; Palop et al., 2007; Corbett et al., 2017; Fu et al., 2019).

To harvest brain tissue, mice were anesthetized and transcardially perfused with ice-cold 0.9% saline. One hemibrain was post-fixed at 4°C using 4% paraformaldehyde in phosphate buffer, and then stored at 4°C in phosphate-buffered saline. The opposite hemibrain was flash-frozen on dry ice and stored at −80°C until use for biochemical experiments. All experiments were carried out in accordance with recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health, under protocol AN-6943 as approved by the Baylor College of Medicine Institutional Animal Care and Use Committee.

Adeno-associated virus (AAV)-mediated gene transfer.

Unless otherwise indicated, mice received infusions of AAV2 serotype viruses targeted to the dentate gyrus (DG). AAVs carried constructs that were previously characterized (Zachariou et al., 2006; Robison and Nestler, 2011) and packaged into AAV2 by the University of North Carolina Vector Core: AAV2-CMV-eGFP (AAV-GFP), AAV2-CMV-ΔFosB-IRES2-eGFP (AAV-ΔFosB), or AAV2-CMV-ΔJunD-IRES2-eGFP. AAV-ΔJunD acts as an inhibitor of ΔFosB activity by binding and preventing dimerization with other AP-1 family transcription factors (Brown et al., 1996). These AAV2 constructs are stably and similarly well-expressed throughout the DG within 18–22 days of infusion (Corbett et al., 2017; You et al., 2017). The inclusion of IRES2 elements allows independent expression of ΔFosB or ΔJunD and eGFP, accounting for the preferential expression of the gene positioned closest to the CMV promoter. Bilateral DG targeting was achieved by stereotaxic infusion of 1 μL of titer-matched (≤ 5×10¹²) virus solution into the DG at rostral (−1.7 mm anterior/posterior (A/P), 1.2 mm medial/lateral (M/L), 2 mm dorsal/ventral (D/V) from bregma) and caudal (−2.7 mm A/P, 2 mm M/L, 2.1 mm D/V from bregma) coordinates. Mice were allowed to express AAVs for either 1 or 2–4 months, until experimentation and/or euthanasia and brain collection. Virus expression was confirmed using immunohistochemical detection of eGFP or ΔJunD. Mice that did not exhibit AAV construct expression in the DG were excluded from analyses.

Electroencephalogram (EEG) recording.

Mice underwent stereotaxic implantation of a six-electrode-array headcap for EEG recordings: two EEG screws were placed over the left and right frontal cortices (A/P, +1.5; M/L, ±1.5), with a depth electrode placed in the left hippocampus (A/P, −2.0; M/L, 2.0; D/V, −1.8). A reference screw and a depth ground electrode were respectively placed over and inside the cerebellum, and a final EEG screw was placed over the right parietal cortex (A/P, −2.0; M/L, 2.0). All EEG screws were wrapped with silver wires connected to a pedestal (Plastics One), and the whole assembly was then secured to the skull via dental cement (Ortho-Jet, LangDental). Mice were allowed to recover for at least 4 days prior to the start of recordings (1 or 2–4 months post-AAV injection) and were recorded over 3-day intervals with at least 3 days of rest in their home cages between sessions. Data was acquired at a sampling rate of 2 kHz. Mice were able to move freely during EEG recordings due to a flexible cable that connects the headcaps to a rotary commutator above the cage. Video-monitoring of EEG recordings was performed in the home cage of each mouse using a Stellate Harmonie monitoring interface (Natus Medical), with video-paired analyses of epileptiform activity in EEG recordings performed using LabChart Pro (AD Instruments), MATLAB (R2021a, The MathWorks), and Spike2 (v7.20, Cambridge Electronic Design).

Seizure phenotype was assessed using LabChart Pro for visual inspection of all EEG channels throughout the entire recording span; recorded seizures were identified as convulsive or non-convulsive through examination of the video recordings. Duration and amplitude of seizures were measured in Spike2. Mean seizure amplitude was calculated as the average of the absolute amplitude values of the hippocampal signal between the beginning and the end of each seizure. To evaluate spectral properties of seizures, power of the hippocampal signal across key frequency ranges (1–5 Hz, 5–10 Hz, 10–20 Hz, 20–50 Hz, 50–80 Hz, and 80–150 Hz) was measured during each seizure using the bandpower command in MATLAB. Seizures were categorized as generalized if observed in all EEG channels and non-generalized if absent in at least one channel. Determination and analysis of epileptiform spike activity was also performed using Spike2 software. For spike quantification, 24 to 72 h of recording from the hippocampal depth electrode were analyzed per mouse and AAV expression time-point. Epileptic spikes were identified according to amplitude criteria. Artifacts, spike-and-wave discharges from seizures, and other physiological events that did not correspond to epileptiform spikes were excluded from the quantification. The total number of epileptiform spike events was quantified, and spike rate was calculated as mean number of events per hour of recording. For quantification of seizures, recordings from mice with 1 month of AAV expression included 19 APP-GFP mice (11 males, 8 females) and 17 APP-ΔJunD mice (8 males, 9 females). Recordings from mice with 2–4 months of AAV expression included 14 APP-GFP mice (8 males, 6 females) and 14 APP-ΔJunD mice (5 males, 9 females). For quantification of epileptiform spike rate, recordings from mice with 1 month of AAV expression included 8 APP-GFP mice (4 males, 4 females) and 8 APP-ΔJunD mice (4 males, 4 females). Recordings from mice with 2–4 months of AAV expression included 7 APP-GFP mice (6 males, 1 female) and 7 APP-ΔJunD mice (2 males, 5 females).

Object location memory testing.

The object location memory test evaluates hippocampal-dependent memory (Kesner et al., 2015) and requires that mice remember the positions of two objects in a controlled cage arena. This test has been used to assess spatial memory in mouse models of AD and epilepsy (Ma et al., 2013; Cho et al., 2015; Corbett et al., 2017; You et al., 2017). For the training trials, two identical objects were placed at adjacent corners of an arena that mice were allowed to explore over 3 trials of 3 minutes each, with 3-min inter-trial intervals. In the testing trial, which occurred 24 hours after the last training trial, mice were placed back into the arena after one object had been displaced to another position. Mice that remember the original locations of the two objects typically spend more time exploring the displaced object than the non-displaced object during the testing phase. Extra-arena spatial cues were used to help orient the mice during training and testing trials. The amount of time each mouse spent with each object in all trials was recorded by an observer blinded to genotype/treatment. Discrimination indices were calculated as the difference between the percent of time spent with displaced object during the training and testing phases of the spatial memory task, and were calculated alongside the total percentages of time spent with the displaced object in the training and testing phases (Fu et al. 2019). Testing of mice with 1 month AAV expression included 8 NTG-GFP (7 males, 1 female), 7 NTG-ΔJunD (2 males, 5 females), 7 APP-GFP (3 males, 4 females), and 6 APP-ΔJunD (3 males, 3 females). Testing of mice with 2–4 month AAV expression included 7 NTG-GFP (2 males, 5 females), 9 NTG-ΔJunD (6 males, 3 females), 8 APP-GFP (3 males, 5 females), and 6 APP-ΔJunD (1 male, 5 females).

Slice electrophysiology recording.

AAV vectors (AAV-CMV-GFP or AAV-CMV-GFP-ΔJunD; UNC Vector Core) or HSV vectors (HSV-CMV-GFP, HSV-CMV-ΔFosB, or HSV-CMV-ΔJunD; Massachusetts General Hospital Gene Delivery Technology Core) were bilaterally infused into the dentate gyrus of the dorsal hippocampus (−2.2 A/P, ±2.4M/L, −2.3 D/V relative to bregma, 10° angle; 0.5 μL per side) and allowed to express for the indicated timeframes. Whole-cell, ex vivo slice electrophysiology was conducted similarly to previously described (Eagle et al., 2018). Briefly, all solutions were bubbled with 95% O₂–5% CO₂ throughout the procedure. Mice were anesthetized with isoflurane and transcardially perfused with sucrose artificial cerebrospinal fluid (aCSF; in mM: 234 sucrose, 2.5 KCl, 1.25 NaH₂PO₄, 10 MgSO₄, 0.5 CaCl, 26 NaHCO₃, 11 glucose). Brains were rapidly removed, blocked, and placed in cold sucrose aCSF. Coronal sections (250 μM) containing dorsal hippocampus were cut on a vibratome (Leica) and transferred to an incubation chamber containing aCSF (in mM: 126 NaCl, 2.5 KCl, 1.25 NaH₂PO₄, 2 MgCl, 2 CaCl, 26 NaHCO₃, 10 glucose) held at 34 °C for 30 min before moving to aCSF at room temperature until used for recordings. Recordings were made from a submersion chamber perfused with aCSF (2 mL/min) held at 30–32°C. Borosilicate glass electrodes (3–6 MΩ) were filled with K-gluconate internal solution (in mM: 115 potassium gluconate, 20 KCl, 1.5 MgCl, 10 phosphocreatine-Tris, 2 MgATP, 0.5 Na₃GTP; pH 7.2–7.4; 280–285 mOsm). GFP-positive cells in the dentate gyrus were visualized with an upright microscope (Olympus) using infrared and epifluorescent illumination. Whole-cell patch-clamp recordings were made from transduced cells using a Multiclamp 700B amplifier and Digidata 1440A digitizer (Molecular Devices) and whole-cell junction potential was not corrected. Traces were sampled (10 kHz), filtered (10 kHz), and digitally stored. Cells with membrane potential more positive than −40 mV or series resistance >30 MΩ were omitted from analysis. Rheobase was measured by giving brief (250 ms) depolarizing (5 pA) steps with 250 ms between steps. Excitability was measured by counting action potentials elicited at escalating depolarizing current steps (0–300 pA, 500 ms) with 30 s inter-step intervals. Peak instantaneous frequency (in Hz) was measured at the current step (between 0–300 pA) that produced the highest peak instantaneous frequency. Maximal current step (in pA) was defined as the step with the highest peak instantaneous frequency.

In vitro assays of neuroprotection in conditions of hyperexcitability.

Primary hippocampal neurons were isolated from E18 Sprague Dawley rats (Envigo), dissociated, and plated in accordance with previously established methods (Kaech and Banker, 2006). Neurons were grown on glass coverslips and incubated in Neurobasal medium (ThermoFisher) with 1X GS-21 supplement (GlobalStem). Half of the medium was replenished every 2–3 days during culturing. Synaptically mature neurons at day in vitro (DIV) 12 were used for experiments. DIV12 neurons were transduced with HSV p1005+ vectors that bicistronically express ΔFosB and eGFP (HSV-ΔFosB) or eGFP alone (HSV-eGFP). These HSV constructs were developed and characterized by the Nestler lab (Berton et al., 2007). Incubation with the virus occurred over 4 hours; maximal neuronal expression occurs in ~6–9 hours and lasts indefinitely in vitro (Neve et al., 2005). Neurons were given 48 hours to recover in conditioned medium after transduction before NMDA (Sigma-Aldrich) application. In vitro experiments were completed in triplicate wells. NMDA was freshly prepared in a 20 mM stock solution and then diluted directly into the culture medium to achieve final concentrations of 25 μM, 50 μM, or 100 μM. Neurons were incubated for 1 hour in medium containing NMDA. NMDA was then washed out and neurons were given 24 hours to recover in conditioned medium. An LDH release toxicology assay kit (Sigma-Aldrich, TOX-7) was used to measure cytotoxicity. The proportion of neurons with HSV expression was measured in 5 replicate samples and averaged. Each replicate assessed 48–94 total MAP2⁺ neurons to calculate the ratio that also expressed either HSV. For immunocytochemistry and pyknotic cell analysis, neurons were washed with ice-cold PBS and fixed for 20 minutes in 4% paraformaldehyde at 4°C. Fixed cells were blocked in 10% normal goat serum before immunocytochemistry with rabbit anti-ΔFosB (Cell Signaling), mouse anti-GFP (3E6; ThermoFisher), and/or chicken anti-MAP2 (EnCor) primary antibodies. Secondary fluorescent labeling was performed with goat anti-rabbit Alexa Fluor 594 (ThermoFisher), goat anti-mouse Alexa Fluor 488 (ThermoFisher), and/or goat anti-chicken Alexa Fluor 594 (ThermoFisher). Labeled neurons were mounted and cured in Prolong Diamond with or without DAPI (ThermoFisher). Fluorescent images were captured via ZEN software (Zeiss), and pyknotic cell counts were performed using the ImageJ (Schneider et al., 2012) software.

Immunohistochemical experiments.

Unless otherwise indicated, tissue preparation and immunohistochemistry were performed as described previously (Corbett et al., 2017; You et al., 2017; You et al., 2018; Fu et al., 2019; Stephens et al., 2020; Jagirdar et al., 2021). Briefly, hemibrains were fixed with 4% paraformaldehyde prior to saturation in 30% sucrose/PBS for 48 hours. Hemibrains were sectioned at a thickness of 30 μm into ten coronal subseries throughout the rostral-caudal extent of the brain using a freezing, sliding microtome. Sections were stored in cryoprotectant medium (30% glycerol, 30% ethylene glycol, 40% PBS) at −20°C until processing. For 3,3-diaminobenzidine (DAB; Sigma-Aldrich) staining of ΔJunD, ΔFosB, NeuN, and cFos, antibodies included: rabbit anti-ΔJunD/JunD (1:5000; Santa Cruz, sc-74) and rabbit anti-ΔFosB (1:5000; Cell Signaling, D3S8R) with biotinylated goat anti-rabbit secondary (1:200; Vector), mouse anti-NeuN (1:30,000; Millipore, MAB337) with biotinylated donkey anti-mouse secondary (1:500; Vector), and goat anti-cFos (1:1000; Santa Cruz, sc-52-G) with biotinylated rabbit anti-goat secondary (1:200; Vector). In most cases, ΔFosB immunoreactivity was quantified as a measurement of mean pixel intensity in the DGC layer. However, due to DGC loss in APP mice with 3 months of AAV-ΔJunD expression, ΔFosB immunoreactivity was quantified in APP-ΔJunD mice as the mean pixel intensity measured within 15 DGCs across intact DG tissue. NeuN immunoreactivity was used to label and measure the thickness of the DGC layer using ImageJ software by experimenters blinded to genotype and treatment. Thickness was measured as the distance between the lateral edge (between the DGC layer and the molecular layer) and medial edge (between the DGC layer and the hilus) of the granule cell layer in two areas each of the upper and lower blades of the DG in two coronal sections, and averaged for each mouse. Samples from mice with 1 mo AAV expression included 7 NTG-GFP (4 males, 3 females), 8 NTG-ΔJunD (3 males, 5 females), 8 APP-GFP (2 males, 6 females), and 8 APP-ΔJunD (6 males, 2 females). Samples from mice with 3 mo AAV expression included 12 NTG-GFP (5 males, 7 females), 15 NTG-ΔJunD (8 males, 7 females), 13 APP-GFP (4 males, 9 females), and 9 APP-ΔJunD (1 male, 8 females). To validate that DG expression of AAV-ΔJunD was able to prevent ΔFosB-induced alteration of target gene expression in our present study, we assessed cFos immunoreactivity (as in Corbett et al., 2017) in a subset of 5 APP mice with 3 mo AAV-GFP expression that had a high level (fold change > 1.5 vs NTG-GFP) of ΔFosB immunoreactivity and in similar subsets of mice from the other genotype/AAV groups, which included 6 NTG-GFP (3 males, 3 females), 6 NTG-ΔJunD (2 males, 4 females), 5 APP-GFP (2 males, 4 females), and 6 APP-ΔJunD (1 male, 5 females).

Gene Ontology network analysis.

The Cytoscape (v3.8.0) application ClueGO (v2.5.8) was used to perform gene ontology (GO) analyses (Shannon et al., 2003; Bindea et al., 2009) on the set of all 2839 genes found via ChIP-seq to be significantly bound by ΔFosB in the hippocampus of APP mice. Using ClueGO, a two-tailed hypergeometric test with a Benjamini-Hochberg correction (Benjamini and Hochberg, 1995) was used to calculate the enrichment of Biological Process GO Terms (ontology version: 5/13/2021) with the target genes bound by ΔFosB in APP mice. ClueGO was also used to generate a GO Network in which GO Terms enriched with ΔFosB target genes are displayed as functionally grouped nodes and are connected by lines/edges that indicate the number of target genes that are shared by connected GO Term nodes. Node size increases as a proportion of the significance of GO Term gene enrichment, and the functional clusters depicted in the network are those that are most representative and/or significantly enriched, simplified to remove redundancy and non-brain organ-specific GO Terms (e.g., “kidney development”). The parameters used to generate the GO Network were selected to maximize the detail-level of GO Terms assessed by the analysis while maintaining the high interconnectivity of the GO Network. Network parameters that were changed from default settings are as follows: FDR < 0.1, GO Level range = 3–20, minimum number of genes in term = 1, minimum percentage of genes in term = 0.1%, kappa = 0.59, and GO Term fusion = TRUE. Subsequent manual analysis of GO Terms and their associated target genes was performed to identify the ΔFosB target genes in APP mice that are implicated in the pathophysiology of disorders with seizure activity (Wang et al., 2017).

Hippocampal RNA extraction and RT-qPCR.

As in previous studies (You et al., 2017; You et al., 2018; Stephens et al., 2020), RNA extraction was performed using adapted instructions from the Qiagen RNeasy Mini kit (74106). Hippocampi were isolated from NTG and APP mice, both male and female, after 1 or 2–4 months of AAV expression. Frozen hippocampi were submerged in RLT/β-mercaptoethanol buffer, finely chopped with small scissors, and homogenized by passing the tissue lysate through an RNA-free 21G needle 15 times. Lysates were centrifuged and supernatants were transferred to new tubes for RNA purification via kit instructions, with RNA eluted in nuclease-free water and checked for concentration using a NanoDrop One spectrophotometer. Reverse transcription was performed according to manufacturer instructions via TaqMan Reverse Transcription Reagent kit (ABI, N8080234), with 2.5 μM random hexamers and oligo d(T)₁₆ per reaction (ABI, N8080127 and N8080128). cDNA samples were then diluted 1:20 in purified water for qPCR reactions performed in triplicate wells with SYBR Green Master Mix (ABI, 4309155) using an ABI StepOnePlus thermocycler. Target gene mRNA expression was calculated using the ΔΔCt RT-qPCR analysis method, with Gapdh mRNA levels used as internal control. Primer sequences used for RT-qPCR experiments are as follows: Gapdh: F, 5’-AATTCAACGGCACAGTCAAGGC-3’ and R, 5’-TACTCAGCACCGGCCTCACC-3’; Hpcal1: F, 5’-CAATGGTTCAAGTGTTCTCG-3’ and R, 5’-TCCTCACAAAGTCATCTGG-3’; Gal: F, 5’-CAACCACAGATCATTTAGCG-3’ and R, 5’-TATAGTGCGGACAATGTTGC-3’; Lrrk2: F, 5’-CACAGCACAATTAGGAAGC-3’ and R, 5’-TGGAAGATTGAGGTCCCA-3’. Samples from mice with 2–4 months of AAV expression included 11 NTG-GFP (5 males, 6 females), 15 NTG-ΔJunD (8 males, 7 females), 13 APP-GFP (4 males, 9 females), and 9 APP-ΔJunD (1 male, 8 females). To validate that DG expression of AAV-ΔJunD was able to prevent ΔFosB-induced alteration of target gene expression in our present study, we performed whole-hippocampal RT-qPCR (as above) in a subset of 4 APP mice with 3 months of AAV-GFP expression that had a high level (fold change > 1.5) of ΔFosB immunoreactivity and in similar subsets of mice from the other genotype/AAV groups. Each subset for this experiment was limited to 4 mice (16 total) to allow all mouse samples to be run on the same RT-qPCR plate, and included 4 NTG-GFP (2 males, 2 females), 4 NTG-ΔJunD (2 males, 2 females), 4 APP-GFP (1 male, 3 females), and 4 APP-ΔJunD (4 females). The primer sequences used for Calb1 RT-qPCR measurement are as follows (Palop et al., 2003): F, 5’-GGAAAGGAGCTGCAGAACTTGAT-3’ and R, 5’-TTCCGGTGATAGCTCCAATCC-3’.

RNA sequencing (RNA-seq).

RNA samples extracted from the DG (~300 ng) of 4-month-old APP mice with high ΔFosB expression and NTG mice (4 per genotype; 1 female and 3 males each) were submitted to the University of Pennsylvania Next-Generation Sequencing Core for library preparation and 100 bp-read depth, paired-read sequencing (Illumina HiSeq 2500). Raw data were analyzed using the Basepair platform with Bowtie: reads were trimmed, aligned to the mm9 mouse genome, and counted using STAR/FeatureCounts. Differential expression analyses (using sex as a secondary factor) were performed using DESeq. Subsequent set-wise overlap analyses of lists of differentially expressed genes and lists of ΔFosB target genes were performed using the default R (R-Core-Team, 2021) and the VennDiagram packages.

Statistics.

Unless otherwise described, statistical analyses were performed using SPSS-23 (IBM) and Prism 9 (GraphPad). Sample sizes were determined based on accumulated empirical data and power analyses used to calculate appropriate numbers of samples necessary to detect significant differences. Unless otherwise noted, results are represented as sample means ± standard error of the means and data are normally distributed. Animals were semi-randomly assigned to experimental groups based on mouse identification number, after balancing groups for age, sex, and genotype. Statistical significance of the overlap between two gene lists was evaluated using two-tailed hypergeometric testing. Where indicated in figure legends, unpaired two-tailed Student’s t-tests were used to compare sample means and chi-square tests were used to compare outcome proportions in studies that involved two experimental groups. For studies that involved more than two experimental groups, 2-factor ANOVA (AAV x genotype) with post hoc Benjamini-Hochberg FDR analyses (p < 0.05) were used to compare sample means between groups. For studies using repeated measures, 2-factor ANOVA with repeated measures (group x current step) followed by post hoc Benjamini-Hochberg FDR analyses (p < 0.05) were used to compare groups. For studies using repeated measures in which experimental group datasets included unequal numbers of observations, a general linear mixed model analysis was used to compare groups. Survival/mortality analyses were performed via Mantel-Cox and Fisher’s Exact testing as indicated in figure legends.

RESULTS

Prolonged inhibition of ΔFosB activity in DGCs exacerbates recurrent seizure activity in APP mice

We previously demonstrated that blockade of ΔFosB activity in dentate granule cells (DGCs) via expression of AAV-ΔJunD for 1 month reversed the epigenetic suppression of two ΔFosB target genes, calbindin and cFos, that are involved synaptic plasticity (Corbett et al., 2017; You et al., 2017). Such normalization of gene expression was accompanied by improvement in spatial memory in APP mice. However, we noted that a number of studies by other groups had demonstrated that the reduction of calbindin and cFos expression is a critical neuroprotective mechanism, especially in conditions of chronic cellular hyperexcitability (Nagerl et al., 2000; Cho et al., 2001; Rawat et al., 2016). We therefore hypothesized that a more prolonged blockade of ΔFosB activity in DGCs may ultimately impair neuroprotective responses and thereby result in hippocampal dysfunction in APP mice.

To test this hypothesis, we expressed AAV-GFP or AAV-ΔJunD (Supplementary Figure 1) in the dentate gyrus (DG) of APP mice for either 1 month (abbreviated blockade) or 2–4 months (prolonged blockade), and then examined effects on overall EEG activity and spatial memory. As previously demonstrated, ΔJunD is an experimental construct that binds to ΔFosB and prevents the epigenetic regulation of its target genes, thereby acting in a dominant-negative fashion to effectively block the actions of ΔFosB in models of addiction as well as AD (Zachariou et al., 2006; Winstanley et al., 2007; Corbett et al., 2017; You et al., 2017). In APP mice, expression of ΔJunD for 1 month did not affect either seizure frequency or convulsive phenotype (Figure 1A–B, D). However, prolonged (2–4 month) expression of ΔJunD increased seizure frequency as well as the proportion of seizures with convulsive phenotype (Figure 1A, C, E). Similarly, prolonged (2–4 month) expression of ΔJunD increased the rate of epileptiform spikes compared to expression of GFP, whereas 1 month expression of ΔJunD did not affect epileptiform spike rate compared to expression of GFP (Figure 1F–G). No significant effects of ΔFosB blockade were observed for seizure duration or absolute amplitude after 1 or 2–4 month AAV expression, and observed power spectra were generally similar regardless of AAV type or duration of expression (Supplementary Figure 2). We noted that whereas observed seizures in APP mice with 1 or 2–4 month expression of AAV-GFP showed a mixture of generalized and non-generalized seizures, all seizures observed in APP mice with 1 or 2–4 month expression of AAV-ΔJunD were generalized (i.e., recorded in all EEG channels, Supplementary Figure 3). We found that the exacerbation of seizures and epileptiform spikes coincided with increased mortality in APP mice expressing ΔJunD (APP-ΔJunD mice) compared to APP mice expressing GFP (APP-GFP mice), as mortality was similar between APP-GFP and APP-ΔJunD mice after 1 month of AAV expression, but was increased in APP-ΔJunD mice by 2.5 months of AAV expression (Figure 1H–J).

To test whether the exacerbated seizure and epileptiform activity induced by prolonged blockade of ΔFosB activity affected hippocampal function, we assessed spatial memory using the object location memory test. We first confirmed our previous findings (Corbett et al., 2017; You et al., 2017) that APP mice expressing AAV-GFP in the DG for 1 month exhibited impaired spatial memory, whereas expression of AAV-ΔJunD for 1 month improved spatial memory in APP mice (Figure 2A, Supplementary Figure 4A). We then assessed the effect of prolonged (2–4 months) expression of ΔJunD on spatial memory. We found that APP mice expressing AAV-ΔJunD for 2–4 months exhibited long-term spatial memory deficits similar to those exhibited by APP mice expressing AAV-GFP for 2–4 month. Together, these results indicate that prolonged blockade of ΔFosB activity does not provide similar beneficial effects as were seen after 1 month blockade of ΔFosB activity (Figure 2B, Supplementary Figure 4B).

Figure 2. — (**A-B**) Spatial memory in the object location memory task was assessed in NTG and APP mice at (A) 1 month or (B) 3 months after AAV injection by calculation of a discrimination index from the difference between the percentage of time spent with the displaced object during the training and testing phases of the task. Bars indicate means ± SEM. Dots indicate individual mice. ***p < 0.001 using Benjamini-Hochberg FDR post hoc test after two-way ANOVA (A-B). For (A), there was a significant effect of genotype [F_(1,24) = 30.43, p < 0.0001], AAV [F_(1,24) = 82.15, p < 0.0001], and interaction [F_(1,24) = 95.03, p < 0.0001]. For (B), there was a significant effect of genotype [F_(1,26) = 203.0, p < 0.0001], but not for AAV [F_(1,26) = 0.2209, p = 0.6423] or interaction [F_(1,26) = 1.024, p = 0.3210].

Overexpression of ΔFosB decreases excitability of DGCs in NTG mice

Since prolonged blockade of ΔFosB activity in DGCs worsened seizure frequency in APP mice, we hypothesized that ΔFosB acts to limit excitability in DGCs, which are major constituents of the “dentate gate” that limits seizure propagation (Heinemann et al., 1992; Lothman et al., 1992; Coulter, 1999; Coulter and Carlson, 2007; Krook-Magnuson et al., 2015). Indeed, in CA1 neurons, overexpression of ΔFosB decreases neuronal excitability whereas overexpression of ΔJunD increases neuronal excitability (Eagle et al., 2018). To determine whether excitability of DGCs is similarly regulated by ΔFosB, we recorded from DGCs in hippocampal slices from NTG mice expressing either ΔFosB or ΔJunD in the DG. We found that DGCs that expressed HSV-ΔFosB showed reduced firing over a range of current steps, whereas DGCs that expressed HSV-ΔJunD showed increased firing, compared to DGCs expressing HSV-GFP (Figure 3A–B). Consistent with these findings, rheobase was elevated in DGCs expressing HSV-ΔFosB compared to those expressing HSV-GFP, but was unaffected in DGCs expressing HSV-ΔJunD (Figure 3C). Membrane resistance was similar in wildtype DGCs regardless of which HSV was expressed (Figure 3D). Notably, the peak instantaneous frequency (inverse of interspike interval) and the maximum current step at which this frequency was recorded each showed a significant decrease in DGCs expressing HSV-ΔFosB vs HSV-ΔJunD (Supplementary Figure 5A–B).

Blockade of ΔFosB activity reveals hyperexcitability of DGCs in APP mice

Because DGCs in naïve APP mice accumulate high levels of ΔFosB due to the spontaneous seizures the mice exhibit (Figure 3E; Corbett et al., 2017; You et al., 2017; You et al., 2018; Stephens et al., 2020), we asked whether DGCs in APP mice also display alterations in neuronal excitability. We found that DGC excitability in APP mice was subtly but consistently reduced over a range of current steps compared to NTG mice (Figure 3F–G), with no significant alterations in rheobase (Figure 3H). However, membrane resistance was increased in DGCs from APP mice compared to DGCs from NTG mice (Figure 3I). Peak instantaneous frequency showed a trend (p = 0.07) for a decrease in naïve APP vs NTG mice, and maximum current step was significantly decreased in naïve APP vs NTG mice (Supplementary Figure 5C–D).

Since DGC excitability was only subtly reduced in APP mice, which typically have high levels of ΔFosB expression, we hypothesized that the accumulation of ΔFosB in DGCs of APP mice could be masking underlying increases in neuronal excitability. To test this hypothesis, we expressed AAV-ΔJunD, or AAV-GFP as control, in the DG of both APP and NTG mice to block ΔFosB and assess if DGC excitability was increased.

Given that prolonged blockade of ΔFosB activity in APP mice can result in exacerbated seizure activity and mortality (Figure 1), we recorded from DGCs in hippocampal slices from NTG and APP mice with 2–4 month blockade of ΔFosB activity to determine whether DGC excitability is altered after prolonged inhibition of ΔFosB activity. We performed ΔFosB immunohistochemistry as a general assessment of relative seizure activity in APP mice. Unexpectedly, we observed that many APP mice with prolonged expression of ΔJunD showed neuroanatomical abnormalities and cell loss in the DGC layer (Figure 3J). As expected, ΔFosB levels were increased in APP mice that expressed AAV-GFP or AAV-ΔJunD relative to baseline levels in NTG-GFP mice, and consistent with exacerbated seizure activity in APP-ΔJunD mice after 3 month AAV expression, levels of ΔFosB were significantly higher in the surviving DGCs of APP-ΔJunD vs APP-GFP mice after 3 month AAV expression (Figure 3K).

We found that prolonged expression of ΔJunD led to increased DGC excitability in NTG and APP mice that could be observed as an increase in number of action potentials elicited over a range of current steps (Figure 3L–N). We also observed significant increases in excitability at higher (125–200 pA) current steps in APP mice expressing ΔJunD rather than APP mice expressing GFP (Figure 3N), although rheobase and membrane resistance were similar across all groups regardless of AAV or genotype (Figure 3O–P) and total number of action potentials fired across all current steps did not differ in APP-ΔJunD vs APP-GFP mice (Supplementary Figure 5E). Consistent with the hypothesis that prolonged DG blockade of ΔFosB could exacerbate seizure activity in APP mice by disinhibiting DGC activity, peak instantaneous frequency and maximum current step were each significantly increased in NTG or APP mice that expressed AAV-ΔJunD vs respective AAV-GFP controls (Supplementary Figure 5F–G).

We also compared the excitability of DGCs in NTG-and APP-GFP mice. There was a trend for a decrease in excitability of DGCs in APP-GFP mice, similar to what was observed in naïve APP and NTG mice, but this effect did not reach significance (Supplementary Figure 5H). We note that the number of cells recorded from in these experiments (n = 10 cells in NTG-GFP, 20 cells in APP-GFP mice) was smaller than the number of cells (n = 34–39) recorded from in naïve mice (Figure 3G).

Given the increased mortality and loss of DGCs observed only in APP mice with prolonged expression of ΔJunD, it is possible that differences in DGC excitability measures are underestimated due to a survivorship bias both in the mice and in the DGCs available to be recorded from. Overall, these results are consistent with the hypothesis that persistent ΔFosB activity limits hyperexcitability in DGCs of APP mice.

ΔFosB is neuroprotective in conditions of excitotoxicity

To quantitatively assess DGC loss after prolonged ΔFosB blockade in APP mice, we measured the average thickness of the DGC layer in NTG or APP mice after 1 month or 2–4 month AAV-ΔJunD or AAV-GFP expression, using NeuN staining to visualize the DGC layer. After 1 month expression of ΔJunD or GFP, there was no difference in the thickness of the DGC layer in either NTG or APP mice (Figure 4A–B), consistent with previous studies that found no DGC loss in this line of APP mice (Chin, 2011; Wright et al., 2013). However, after 2–4 months of expression of ΔJunD or GFP, APP mice that received ΔJunD exhibited a marked reduction in DGC layer thickness compared to all other groups (Figure 4C–D). These results suggest that ΔFosB serves a neuroprotective role in conditions of chronic overexcitation. Indeed, ΔFosB may exert neuroprotection via epigenetic suppression of cFos and calbindin, two identified targets of ΔFosB that have been linked to neuroprotection. Consistent with this hypothesis, we found that whereas APP mice expressing GFP for 2–4 months exhibit reduced expression of cFos and calbindin compared to NTG mice expressing GFP for 2–4 months, APP mice expressing ΔJunD for 2–4 months had similar levels of calbindin and even higher levels of cFos compared to NTG mice expressing GFP or ΔJunD for 2–4 months (Supplementary Figure 6). Therefore, prolonged blockade of ΔFosB activity leads to de-repression of cFos and calbindin expression, coinciding with loss of neuroprotective programs.

Figure 4. — **(A-D)** Representative NeuN immunostaining and quantification of the average thickness of the dentate granule cell layer (DGCL) in NTG and APP mice with (A-B) 1 month or (C-D) 3 month expression of AAV-GFP or AAV-ΔJunD. Scale bar = 125 μm. (E) Timeline of experimental procedures to measure markers of cell stress under NMDA challenge in primary hippocampal neurons that express HSV-GFP or HSV-ΔFosB. (**F-G**) (F) Example images and (G) quantification demonstrating similar expression of both HSVs in primary neurons. Arrows indicate transduced neurons expressing GFP reporter, arrowheads indicate non-transduced neurons. Scale bar = 125 μm. (H) Example images showing healthy versus pyknotic neurons. Arrow indicates condensed chromatin, arrowhead indicates hyperintensity of MAP2 staining and neurite retraction. Scale bar = 20 μm. (I) Proportions of GFP- or ΔFosB-expressing neurons identified as pyknotic at escalating doses of NMDA. (J) Comparison of lactate dehydrogenase (LDH) release from GFP- or ΔFosB-expressing neurons at escalating doses of NMDA. “Virus Only” (VO) denotes a control condition with no vehicle washes (I-J). Data illustrate means ± SEM. Dots indicate individual mice. ***p < 0.001 using Benjamini-Hochberg post hoc test (B, D) or *p < 0.05, **p < 0.01 using Tukey’s post hoc test (I-J) after two-way ANOVA. For (B), there was no significant effect of genotype [F_(1,27) = 1.131, p = 0.2969], AAV [F_(1,27) = 0.01797, p = 0.8944], or interaction [F_(1,27) = 0.1790, p = 0.6756]. For (D), there was a significant effect of genotype [F_(1,45) = 25.15, p < 0.0001], AAV [F_(1,45) = 18.28, p < 0.0001], and interaction [F_(1,45) = 5.433, p = 0.0243]. For (I), there was a significant effect of NMDA dose [F_(4,40) = 63.58, p < 0.0001], HSV [F_(1,49) = 11.88, p = 0.001], but no effect for interaction [F_(4,40) = 1.456, p = 0.234]. For (J), there was a significant effect of NMDA dose [F_(3,16) = 140.0, p < 0.0001], HSV [F_(1,23) = 10.00, p = 0.006], but no effect for interaction [F_(3,16) = 0.007, p = 0.632].

To directly test whether ΔFosB provides protection to neurons in excitotoxic conditions, we examined whether overexpression of ΔFosB could protect primary hippocampal neurons in an in vitro assay of excitotoxicity. Primary hippocampal neurons were grown in vitro for 12 days prior to exposure to either HSV-GFP or HSV-ΔFosB for 4 hours, followed by NMDA challenge 2 days later (Figure 4E). HSV was used instead of AAV for this assay due to the reliability of expression in vitro. We confirmed that both GFP and ΔFosB were expressed effectively and to similar extents in our model system (Figure 4F–G) and quantified the proportions of neurons that expressed either GFP or ΔFosB that were healthy (intact processes and nuclei) or pyknotic (condensed processes and nuclei; Figure 4H). We used two negative control conditions to ensure that any differences detected were due to neuroprotection from excitotoxicity and not from general physical disturbance of the media: “Virus Only (VO)”, in which no vehicle solution was applied, and “0 μM NMDA”, in which vehicle solution containing no NMDA was applied. We found that the proportion of ΔFosB-expressing neurons exhibiting pyknosis was significantly lower than the proportion of GFP-expressing neurons with pyknosis under escalating doses of 25 and 50 μM NMDA, but we observed no differences in pyknosis at higher (100 μM) dosages (Figure 4I). Similarly, release of lactate dehydrogenase (LDH), a cell stress marker, was also significantly reduced in neurons expressing ΔFosB relative to neurons expressing GFP at a dosage of 50 μM NMDA, although there were no differences in LDH release at higher doses (Figure 4J). Overexpression of ΔFosB may also provide some protection against any detrimental effect of physical disturbance of the media, given that ΔFosB-expressing neurons showed less LDH release than GFP-expressing neurons after a wash with 0 μM NMDA vehicle solution (Figure 4J). Together, these results suggest that persistent ΔFosB activity is necessary to provide neuroprotection under conditions of hyperexcitability in the DG.

ΔFosB epigenetically regulates hippocampal gene expression via discrete modes of gene regulation

To identify subsets of ΔFosB target genes that could underpin putative mechanisms of neuroprotection against hyperexcitability, we performed new Gene Ontology (GO) analyses of hippocampal ΔFosB target genes bound in APP mice, derived from our previous ΔFosB chromatin immunoprecipitation-sequencing (ChIP-seq) data from whole hippocampal samples from APP mice (Stephens et al., 2020). We began our GO analyses using the list of all 2839 gene targets of ΔFosB in APP mice, then generated a GO sub-network (Figure 5A; additional network details in Table 1 and Supplementary File 1) solely of the GO terms that contained genes that encode for or regulate ion channels, ion transporters, or proteins involved in processes of neuroprotection against neuronal hyperexcitability, such as inhibitory neuropeptide signaling. We found that 45% (1287 of 2839 genes) of ΔFosB target genes in APP mice could be categorized in this manner. In addition, many of these target genes are known to be involved in the pathophysiology of epilepsies and other disorders with seizure activity (Table 1; Wang et al., 2017).

Figure 5. — (A) Biological Process Gene Ontology (GO) network of GO Terms (nodes) that are enriched by ChIP-seq-identified ΔFosB target genes in APP mice that encode or regulate ion channels, transporters, and pathways known to impact neuronal excitability. The size of GO Term nodes indicates levels of significance (lower p-values have bigger nodes), and nodes are connected by lines whose thickness denotes numbers of genes that are shared between nodes. (**B-D**) Benchtop RT-qPCR quantifications showing the impact of 3 month AAV-GFP or AAV-ΔJunD expression on hippocampal mRNA expression of ΔFosB target genes (B) *Hpcal1*, (C) *Gal*, and (D) *Lrrk2* in NTG and APP mice. Bars indicate means ± SEM. Dots indicate individual mice. *p < 0.05, **p < 0.01 using Benjamini-Hochberg post-hoc test after two-way ANOVA (B-D). For (B), there was a significant effect of genotype [F_(1,43) = 4.816, p = 0.0336] and AAV [F_(1,43) = 5.076, p = 0.0296], but no effect of interaction [F_(1,43) = 1.175, p = 0.2844]. For (C), there was a significant effect of genotype [F_(1,43) = 10.41, p = 0.0024] and AAV [F_(1,43) = 5.670, p = 0.0218], but no effect of interaction [F_(1,43) = 3.561, p = 0.0659]. For (D), there was no significant effect of genotype [F_(1,43) = 1.495, p = 0.2280], AAV [F_(1,43) = 0.2335, p = 0.6314], or interaction [F_(1,43) = 0.09933, p = 0.7542].

Table 1.

A subset of ΔFosB target genes bound in APP mice that relate to GO Biological Processes of neuronal excitability/neurotransmission includes many epilepsy-related genes.

Gene Ontology (GO) Terms	Highlighted ΔFosB target genes in APP mice
Acetylcholine receptor signaling pathway	*Chrm3, Chrna7*, Ly6a, Ly6c1, Ly6c2, Ly6f, Ly6h, Oprm1, Plcb1
Adenylate cyclase inhibitor activity	*Adgrv1, Grm7*
Cellular glucuronidation	*Prkce*, Ugt1a6b, Ugt1a7c, *Ugt1a9, Ugt1a10*, Ugt2a1, Ugt2a2, Ugt2a3
Cellular response to calcium ion	Adcy8, *Adgrv1*, Akr1c18, Alox5ap, Asph, *Braf*, Cpne2, Crp, Iqgap1, *Kcnh1, Mef2a,* *Mef2c, Nrxn1, Ryr3*, Syt1, Syt17, *Syt4*, Wnk1, Wnt5a
Cellular transition metal ion homeostasis	*Atp7b, Heph*, Nubp1, Slc39a10
cGMP-dependent protein kinase activity G protein-coupled receptor activity or G protein-coupled receptor signaling pathway G protein-activated inward rectifier potassium channel activity	*Prkg1, Prkg2* *Adcy2, Adcy8, Adgrv1, Calcr, Chrm3, Cx3cr1, Ece1, Gal, Grm5, Grm7, Homer1, Htr1f, Htr2c, Insr, Kcnk2, Oprm1, P2ry10, P2ry10b, Pde4b, Plcb1, Ptgdr2, Ptger1, Tac1, Vip* *Kcnj3, Kcnj5, Kcnj6*
Histamine metabolic process	*Hnmt*, Prg3, *Trh*
Neuropeptide catabolic process	Ctsh, *Ece1*
Organic cation transmembrane transporter activity	*Slc5a7* , Slc22a1, Slc22a2, Slc22a3, Slc25a17, Slc25a29, Slc25a47, Slc44a1
Organic cation transport	Abcb1a, *Htr2c, Pdzk1, Slc5a7*, Slc22a1, Slc22a2, Slc22a3, Slc25a17, Slc25a29, Slc25a47, Slc44a1
Prostaglandin receptor activity	Hpgd, *Ptgdr2, Ptger1*, Ptger2, Slc22a22
Prostaglandin E receptor activity	Hpgd, *Ptger1*, Ptger2
Quaternary ammonium group transport	*Pdzk1, Slc22a1, Slc22a2, Slc22a3, Slc25a29, Slc25a47*
Regulation of synapse structure or activity	Adgrb3, Adgre5, Adgrl3, Arf4, Asic2, *Bdnf*, C1ql3, *Cask, Chrna7*, Cntnap4, Ctnna2, Dab2ip, Dhx36, Dlg5, *Dnm1l, Dnm3*, Flrt2, Gpm6a, Homer1, Il1rap, *Il1rapl1*, Il1rapl2, Lrfn5, *Lrrk2, Magi2*, Mdga2, *Mef2c*, Mfn1, *Nrxn1, Opa1*, Ptprd, Ptpro, Ptprt, Rheb, Slit1, Slitrk3, Slitrk4, Snap91, Sybu, Thbs2, Tiam1, Tpbg, *Vps35*, Wnt5a, Xlr3b, Xlr3c, Xlr4b, *Zmynd8*
Regulation of voltage-gated sodium channel activity	*Fgf12*, Fgf13, Fgf14, *Scn1b*
Response to calcium ion	Adcy8, *Adgrv1*, Akr1c18, Alox5ap, Asph, *Braf*, Cpne2, Crp, *Hcn1*, Homer1, *Il6*, Iqgap1, *Kcnh1, Kcnmb2*, Mef2a, *Mef2c, Nrxn1, Pcdh15*, Pde1c, Pef1, Ryr2, *Ryr3*, Sucnr1, Syt1, Syt17, *Syt4,* Tph2, Tshb, Wnk1, Wnt5a
Retrograde trans-synaptic signaling by neuropeptide	*Bdnf, Syt4*
Serine-type endopeptidase inhibitor activity	A2m, *Serpina5, Serpinf1*
Signal transduction	Acvr1c, *Adgrv1*, Arhgap29, Arhgap36, Bcl6, *Bdnf*, Bmp3, *Braf*, Camk4, Cdh13, *Chrm3*, Chrna6, *Chrna7, Chrnb3*, Chrnb4, *Ctnnd2*, Cxcl12, *Dcx, Dgkd, Dnm1l, Dnmt1, Ece1, Elmo1, Erbb4, Ercc6, Ezh2, Fat4, Fgf12, Gabrg2, Gal, Gipc1, Gnao1, Gria3, Grm5, Grm7, Htr2c*, Iigp1, *Il1b*, Il1r1, Il1rap, *Insr, Kcnh1, Kdm6a, Lrrk2, Mef2c, Mllt3, Mrap, Nfatc1, Nras, Nrg3*, Onecut1, *Opa1, Ophn1, Oprm1*, Pde4b, Pde7b, *Plcb1, Prkce, Ptgdr2, Ptger1, Ptpn5, Rrm2b, Ryr3, Srgap2*, Stc1, *Tcf4, Vps35*, Wnk1
Trans-synaptic signaling by endocannabinoid	*Grm5, Nrxn1*, Pcdha4, *Plcb1*
Transport or vesicle-mediated transport	Ano2, *Atp7b, Cask*, Cdh13, *Chrm3*, Chrna6, *Chrna7, Chrnb3*, Chrnb4, *Csnk1g1*, Cxcl12, *Dmd, Dnajc6, Dnm1l, Dnm3, Elmo1, Erbb4, Exoc6, Exoc6b, Fgf12, Fmn2*, Gabra3, *Gabrg2, Gal, Gnao1*, Grem1, *Gria3*, Grid1, *Grm5, Grm7, Hcn1, Heph, Htr2c, Il1b, Il1rapl1, Insr*, Kcnb2, Kcnc2, *Kcnd2, Kcne1*, Kcne1l, Kcne2, *Kcnh1, Kcnh2*, Kcnh7, *Kcnj3, Kcnj5, Kcnj6*, Kcnk2, Kcnmb2, *Kcnq3, Kcnq5, Lrrk2, Magi2, Mef2c, Nkain3, Nrxn1, Opa1, Ophn1, Oprm1, Pdzk1, Plcb1, Ppt1, Prkce, Prkg2, Ptger3, Ptpn5*, Rab18, *Ryr3, Scn1b, Slc1a4, Slc26a1, Slc4a10, Slc9a9*, Sorcs1, Sv2b, *Syt4, Thoc2, Trpc5, Trpc6, Trpc7, Trpm3, Vip, Vps35*, Wnk1, Xk

Open in a new tab

Bold = known epilepsy-associated target gene

To begin to assess whether ΔFosB may exert neuroprotective actions by altering the expression of the 1287 target genes identified above, we re-examined previous RNA-sequencing data from DG tissue taken from NTG and APP mice (Stephens et al., 2020). Unexpectedly, we found that only 1.5% (20 of 1287 genes) showed altered mRNA expression (9 upregulated, 11 downregulated) in APP versus NTG mice. Instead, most ΔFosB targets in the DG of APP mice showed similar levels of mRNA expression levels compared to NTG mice.

Although previous studies into ΔFosB-driven regulation of hippocampal gene expression have highlighted ΔFosB’s ability to epigenetically alter target gene expression (Chen et al., 2000; Robison and Nestler, 2011; Gajewski et al., 2016; Corbett et al., 2017; You et al., 2017; You et al., 2018; Stephens et al., 2020), some transcription factors have also been demonstrated to be able to stabilize, rather than alter, gene expression (Kadkhodaei et al., 2013; Gurdon et al., 2020). We therefore investigated the possibility that persistent ΔFosB activity may act in multi-modal fashion to either alter or stabilize gene expression. To do so, we examined the resulting patterns of gene expression in the hippocampus of NTG or APP mice after 3 month expression of GFP or ΔJunD in the DG. To validate that prolonged blockade of ΔFosB activity by AAV-ΔJunD was effective at preventing alteration of target gene expression by ΔFosB in APP mice, we confirmed that expression of the known ΔFosB target genes cFos and calbindin were reduced in APP mice expressing GFP for 3 months, compared to NTG mice expressing GFP for 3 months, consistent with our previous findings (Supplementary Figure 6; Corbett et al., 2017; You et al., 2017). In contrast, cFos and calbindin expression were not reduced in APP mice expressing ΔJunD for 3 months (Supplementary Figure 6).

Prolonged blockade of ΔFosB activity revealed three patterns of gene expression. For some genes, for example the gene that encodes hippocalcin-like protein 1 (Hpcal1), APP mice with 3 months of GFP expression showed significant reductions in mRNA relative to GFP-expressing NTG mice, whereas expression of ΔJunD for 3 months restored expression levels in APP mice back to NTG levels (Figure 5B), suggesting that ΔFosB promotes differential expression of Hpcal1 in APP mice. Expression of other genes, such as the one that encodes for the inhibitory neuropeptide galanin (Gal), showed no changes in APP mice with 3 months of GFP expression (Figure 5C), suggesting that in APP mice, ΔFosB maintains expression of Gal at NTG levels. However, 3 months of ΔJunD expression to block ΔFosB activity resulted in markedly reduced levels of galanin expression in APP, but not NTG, mice (Figure 5C). Finally, some genes such as the one that encodes for leucine-rich repeat kinase 2 (Lrrk2) were previously found to be bound by ΔFosB in the hippocampus of APP mice (Stephens et al., 2020) but did not show alterations in mRNA levels between APP and NTG mice regardless of expression of GFP or ΔJunD (Figure 5D), suggesting that ΔFosB binds to Lrrk2, but does not by itself modulate its expression. Taken together, these results indicate that ΔFosB binding to target genes may result in discrete modes of gene expression regulation that can be revealed by prolonged blockade of ΔFosB activity (Figure 6).

Figure 6. — In conditions with recurrent seizures, ΔFosB accumulates in hippocampal neurons and binds at target gene loci. ΔFosB then recruits other factors such as co-factors or histone-marking enzymes to epigenetically regulate gene expression in discrete modes that could, for example, stabilize expression or alter expression of different target genes. Such regulation occurs over different timescales, which may reflect cellular conditions or availability of binding partners. Persistent epigenetic regulation by ΔFosB can coordinate programs of cellular function that regulate neuronal excitability and viability, while impairing synaptic plasticity and cognition, to generate a net neuroprotective response against hyperexcitability and excitotoxicity in the contexts of recurrent seizures such as those that occur in AD and in epilepsy. Given the breadth of genes bound by ΔFosB, other impacts of ΔFosB-induced epigenetic regulation are likely to exist as well and remain to be characterized.

DISCUSSION

We previously demonstrated that the spontaneous seizures that occur in mouse models of AD as well as mouse models of epilepsy lead to hippocampal accumulation of ΔFosB, an activity-dependently expressed transcription factor with a long half-life (Corbett et al., 2017; You et al., 2017; You et al., 2018; Stephens et al., 2020). We found that ΔFosB epigenetically regulates gene expression, and suppression of plasticity-related target genes such as calbindin and cFos contributed to seizure-induced memory impairments in APP mice. Notably, blockade of ΔFosB activity for 1 month restored gene expression of calbindin and cFos and improved hippocampus-dependent memory, without affecting the spontaneous epileptiform activity exhibited by APP mice (Corbett et al., 2017; You et al., 2017). However, given the well-documented role that the suppression of calbindin plays in the neuroprotective response of neurons to chronic excitotoxicity (Nagerl et al., 2000), we hypothesized that ΔFosB may coordinate neuroprotective responses over longer timescales. In the current work, we tested this hypothesis by examining the consequences of prolonged inhibition of ΔFosB in the DG of APP mice. Prolonged inhibition of ΔFosB activity for 2–4 months resulted in exacerbation of seizures and epileptiform spikes, and premature mortality; resulted in neuronal cell death of DGCs; and was not associated with improvement in hippocampal memory. Overall, these results suggest a model in which recurrent seizures induce expression of ΔFosB, which due to its unusually long half-life, acts over long timescales (days to weeks) to epigenetically regulate gene expression and promote neuroprotection in conditions of chronic hyperexcitability or excitotoxicity, and may act at the cost of synaptic plasticity and cognition (Figure 6).

Our interpretation of the findings that in APP mice, an abbreviated blockade of ΔFosB activity (1 month) was beneficial to cognition whereas prolonged blockade of ΔFosB activity (2–4 months) was detrimental, is that plasticity and neuroprotection may work under different timescales. The abbreviated blockade of ΔFosB activity was sufficient to restore expression of targets that are epigenetically suppressed by ΔFosB, including both cFos and calbindin, which may acutely allow for the activity-dependent gene expression necessary for plasticity. However, the restoration of these gene targets, particularly calbindin, also results in loss of the neuroprotective restriction of calcium influx, and eventually sensitizes neurons to excitotoxicity and neuronal death. Under normal conditions, calbindin expression is particularly high in the DG, which has been characterized for its ability to dynamically down-regulate calbindin as a compensatory response to chronic hyperexcitability and excitotoxicity (Nagerl et al., 2000). Calbindin is downregulated in the DG of individuals with AD as well as in mouse models (Palop et al., 2003; Chin et al., 2005; Palop et al., 2007; Sanchez et al., 2012; Hall et al., 2015; You et al., 2017; Johnson et al., 2020), and it is noteworthy that the DG is particularly resistant to cell death in AD and in epilepsy, and in related mouse models (Meldrum, 1993; Magloczky et al., 1997; Blumcke et al., 1999; Nagerl et al., 2000; Wright et al., 2013). In our current study, prolonged blockade of ΔFosB in the DG of APP mice resulted in restoration of calbindin expression and unusual loss of DGCs, underscoring the role of ΔFosB in providing neuroprotection in excitotoxic conditions. These findings are consistent with our recent findings that prolonged blockade or reduction of ΔFosB in either APP mice or a pilocarpine model of epilepsy prevented compensatory NPY expression and mossy fiber sprouting, as well as exacerbated neuroinflammation (Clasadonte et al., 2023).

The sparse activity of the DG and the ability of DGCs to extensively regulate calcium signaling contribute to its resilience against hyperexcitability, and allow the DG to serve as a “gate” that can limit further progression of seizure activity into the hippocampus (Heinemann et al., 1992; Lothman et al., 1992; Coulter, 1999; Coulter and Carlson, 2007; Krook-Magnuson et al., 2015). The robust increase in ΔFosB expression in DG induced by seizures may be a feedback mechanism by which the DG controls DGC excitability and further strengthens the “dentate gate”. We found that even in NTG wild-type mice, expression of ΔFosB reduced neuronal excitability of DGCs, whereas blockade of ΔFosB activity increased neuronal excitability of DGCs, consistent with the hypothesis that the induction of ΔFosB by seizures may serve as a compensatory feedback mechanism. Notably, in APP mice, which have spontaneous seizures and high levels of ΔFosB in DGCs, the excitability of DGCs was subtly reduced compared to NTG mice, as would be expected if the high levels of ΔFosB act to control neuronal excitability.

Blockade of ΔFosB activity in both NTG and APP mice increased neuronal excitability as predicted. Surprisingly, the increase in DGC excitability was not greater in APP mice than it was in NTG mice, as we first predicted it would be. However, it is important to note that there may be a survivorship bias in these results: there was cell loss and greater mortality in APP mice that were subject to prolonged blockade of ΔFosB activity. The DGCs we recorded from in the slice physiology experiments were cells that had survived the 2–4 month post-injection period, from mice that survived 2–4 months post-injection. It is likely that a proportion of DGCs had sufficient hyperexcitation to induce cell death, and had died prior to our recordings. Our recordings may therefore be biased toward DGCs that may have been more adept at restricting hyperexcitability despite prolonged blockade of ΔFosB activity, and were taken from APP-ΔJunD mice that survived until the slice recordings at 2–4 months post-injection.

Nonetheless, our results are overall consistent with past studies suggesting that seizure-induced ΔFosB may promote molecular and physiological adaptations to electroconvulsive shock, and with studies showing that FosB-knockout mice exhibit spontaneous recurrent seizure activity (Chen et al., 1995; Hiroi et al., 1998; Yutsudo et al., 2013). The current results in the DG are also consistent with our previous findings that overexpression of ΔFosB restricted, whereas ΔFosB blockade disinhibited, neuronal excitability and firing activity over a range of current steps also in CA1 pyramidal cells (Eagle et al., 2018). In addition, ΔFosB may exert neuroprotective effects by regulating the production of newborn neurons, which have been demonstrated to limit activity of mature DG neurons (Ikrar et al., 2013; Adlaf et al., 2017; Jain et al., 2019; Berdugo-Vega et al., 2020; McHugh et al., 2022). Indeed, neurogenesis is impaired by knockout of FosB (Yutsudo et al., 2013; Manning et al., 2019), and is aberrantly high in young APP mice that exhibit spontaneous seizures and high expression of ΔFosB (Fu et al., 2019). Moreover, we previously reported that ΔFosB binds to a number of genes that can regulate neurogenesis in APP or pilocarpine-treated mice (Stephens et al., 2020). Since neurogenesis itself can contribute to neuroprotection (Kurushima et al., 2005; Choi et al., 2018), it is possible that prolonged blockade of ΔFosB activity may have contributed to neuronal death by preventing the engagement of this mode of protection. Together, our results demonstrate that ΔFosB may indeed contribute to the naturally low excitability of DGCs, and that ΔFosB activity is necessary to control DGC hyperexcitability and restrict seizure activity in APP mice.

Our gene ontology analyses of hippocampal ΔFosB target genes in APP mice showed that almost half of the currently identified ΔFosB target genes in the DG of APP mice were related to pathways that regulate neuronal excitability and/or neuroprotection under conditions of hyperexcitability. These target gene analyses therefore allowed us to identify putative ΔFosB target gene pathways that neurons may use to naturally limit their own excitability. However, less than 10% of the 1287 ΔFosB target genes related to excitability in APP mice showed alterations in mRNA levels compared to NTG mice in RNA-seq analyses from DG samples. This low proportion of overlap could result from relatively small sample sizes, the fact that the ChIP-seq was performed on hippocampal samples whereas the RNA-seq was performed on DG samples, or represent a multi-modal means of gene regulation exerted by ΔFosB. Our results align with past studies showing that another epilepsy-related transcription factor, NRSF/REST, represses the expression of only ~10% of its target genes (McClelland et al., 2014). Indeed, ΔFosB, as part of the AP-1 transcription factor complex, has been hypothesized to be a pioneer transcription factor that is required in numerous contexts to help stabilize target gene expression by opening and maintaining chromatin accessibility at target genes and enhancers, but does not itself alter gene expression (Biddie et al., 2011; Vierbuchen et al., 2017; Bejjani et al., 2019; Iwafuchi-Doi, 2019). Some activity-induced AP-1 factors, including ΔFosB, are thought to directly mediate and maintain chromatin alterations induced by neuronal activity or seizures (Malik et al., 2014; Su et al., 2017; Fernandez-Albert et al., 2019). ΔFosB may also indirectly modulate chromatin remodeling via regulation of epilepsy-related target gene pathways in APP mice that impact chromatin remodeling, such as those involving Ezh2, Dnmt1, and Clock (Baets et al., 2015; Li et al., 2017; Khan et al., 2019; Stephens et al., 2020; Yeh et al., 2023).

We hypothesized that if persistent ΔFosB activity stabilizes target gene expression in APP mice in a manner that limits seizures and excitotoxicity, then prolonged ΔFosB blockade should reveal alterations in expression of target genes related to excitability and neuroprotection that otherwise show stable expression in APP mice with intact ΔFosB activity. We found that galanin mRNA levels are reduced exclusively in APP mice with prolonged ΔFosB blockade, demonstrating that ΔFosB acts through discrete modes of regulation that can stabilize target gene expression. Galanin is a soluble inhibitory neuropeptide (Kask et al., 1995) that we and others have identified as a ΔFosB target gene (Anouar et al., 1999; Yutsudo et al., 2013; Stephens et al., 2020), and that is acutely upregulated by, released during, and acts to limit seizure activity in patients and mouse models of temporal lobe epilepsy (Mazarati et al., 1998; Mazarati, 2004; Wang et al., 2010; Guipponi et al., 2015). If persistent ΔFosB activity stabilizes galanin expression to help limit seizures and excitotoxicity, we would expect to see a reduction in galanin expression only in APP mice that have had ΔFosB blocked long enough to show exacerbated seizure activity and neuron loss (2–4 months), which we indeed observed (Figure 5C).

Persistent ΔFosB activity may also help to limit seizure activity and excitotoxicity through other discrete modes of regulation, including the classical mode in which ΔFosB directly alters target gene expression, and another mode in which ΔFosB binding may act in redundancy with other pathways to maintain target gene expression, i.e., when ΔFosB activity alone is not required for stability. The idea that persistent ΔFosB activity restricts expression of calcium-binding Hpcal1 in ways that support neuroprotection in APP mice (classical mode) is consistent with our past findings showing that ΔFosB-driven reduction of another calcium-binding protein, calbindin, promotes neuroprotection in AD patients and mouse models (You et al., 2017). This idea is also in line with findings that Hpcal1 is involved in activity-dependent homeostatic scaling (Schanzenbacher et al., 2016) and may promote neuroprotection in AD patients (Braunewell, 2012). We also hypothesize that ΔFosB may act through a redundant mode of epigenetic regulation for target genes that show stable expression in APP mice and that are not impacted by prolonged ΔFosB blockade. It may be adaptive for ΔFosB to act through a redundant mode in concert with other factors to stabilize expression of genes that are critical for neuronal function and survival. For example, Lrrk2 is a known Parkinson’s- and emerging Alzheimer’s-associated gene (Zhao et al., 2011; Aasly et al., 2012; Li et al., 2013; Chen et al., 2017; Giau et al., 2019; Wang et al., 2019) that is expressed at similar levels in NTG and APP mice, and shows stable expression following 3 months of ΔFosB blockade in APP mice.

These results highlight putative mechanisms that exhibit varying degrees of epigenetic plasticity, a term that describes the ease by which mechanistic steps required to produce a given change in genome topology can occur, with each step requiring a specific duration of time that must elapse prior to observing a given change in gene topology (Flavahan et al., 2017). Mechanisms of epigenetic plasticity can include the ease with which a specific gene or histone is methylated, the accessibility of a gene for initial activation by pioneer transcription factor complexes, the latency from an epigenetic alteration to a chromatin rearrangement, the latency from chromatin rearrangements to downstream changes in gene expression, the accessibility of required enhancer configurations, and other mechanisms. A subset of ΔFosB target genes that have less epigenetic plasticity may therefore take longer to show alterations in expression or in downstream impacts on neuronal function following ΔFosB accumulation or blockade. ΔFosB-driven alterations in discrete aspects of neuronal or cognitive function may thus be expected to emerge over different durations, depending on the functions served by the specific target genes that are regulated by ΔFosB over specific intervals of time.

Together, our results demonstrate that persistent ΔFosB activity restricts DG excitability, limits seizure activity, and confers neuroprotection in the DG of APP mice. ΔFosB may use discrete modes of target gene regulation to exert durable combinatorial control over a subset of genes involved in neuronal excitability and neuroprotection. Future studies to identify and characterize these gene targets may reveal novel endogenous pathways by which neurons may restrict their own excitability under conditions of recurrent seizure activity.

Supplementary Material

Stephens et al 2024 Figures Suppl

NIHMS2018836-supplement-Stephens_et_al_2024_Figures_Suppl.pdf^{(3.7MB, pdf)}

Suppl File 1

NIHMS2018836-supplement-Suppl_File_1.xls^{(60.5KB, xls)}

Highlights.

Seizure-induced expression of ΔFosB epigenetically regulates hippocampal gene expression via discrete modes of gene regulation.
Blockade of ΔFosB signaling increases neuronal excitability of dentate granule neurons in APP mice.
Prolonged blockade of ΔFosB signaling exacerbates spontaneous seizures in APP mice.
Epigenetic regulation of gene expression by ΔFosB coordinates neuroprotection over long timescales.

Funding:

This work was supported by the National Institutes of Health grants NS085171, NS086965, and AG065290 (JC), and AG063462 (GS).

REFERENCES

Aasly JO, Shi M, Sossi V, Stewart T, Johansen KK, Wszolek ZK, Uitti RJ, Hasegawa K, Yokoyama T, Zabetian CP, Kim HM, Leverenz JB, Ginghina C, Armaly J, Edwards KL, Snapinn KW, Stoessl AJ, Zhang J, 2012. Cerebrospinal fluid amyloid beta and tau in LRRK2 mutation carriers. Neurology 78, 55–61. [DOI] [PMC free article] [PubMed] [Google Scholar]
Adlaf EW, Vaden RJ, Niver AJ, Manuel AF, Onyilo VC, Araujo MT, Dieni CV, Vo HT, King GD, Wadiche JI, Overstreet-Wadiche L, 2017. Adult-born neurons modify excitatory synaptic transmission to existing neurons. Elife 6, e19886. [DOI] [PMC free article] [PubMed] [Google Scholar]
Altuna M, Giménez S, Fortea J, 2021. Epilepsy in Down Syndrome: A Highly Prevalent Comorbidity. J Clin Med 10, 2776. [DOI] [PMC free article] [PubMed] [Google Scholar]
Amatniek JC, Hauser WA, DelCastillo-Castaneda C, Jacobs DM, Marder K, Bell K, Albert M, Brandt J, Stern Y, 2006. Incidence and predictors of seizures in patients with Alzheimer’s disease. Epilepsia 47, 867–872. [DOI] [PubMed] [Google Scholar]
Anouar Y, Lee HW, Eiden LE, 1999. Both inducible and constitutive activator protein-1-like transcription factors are used for transcriptional activation of the galanin gene by different first and second messenger pathways. Mol Pharmacol 56, 162–169. [DOI] [PubMed] [Google Scholar]
Baets J, Duan X, Wu Y, Smith G, Seeley WW, Mademan I, McGrath NM, Beadell NC, Khoury J, Botuyan MV, Mer G, Worrell GA, Hojo K, DeLeon J, Laura M, Liu YT, Senderek J, Weis J, Van den Bergh P, Merrill SL, Reilly MM, Houlden H, Grossman M, Scherer SS, De Jonghe P, Dyck PJ, Klein CJ, 2015. Defects of mutant DNMT1 are linked to a spectrum of neurological disorders. Brain 138, 845–861. [DOI] [PMC free article] [PubMed] [Google Scholar]
Bakker A, Albert MS, Krauss G, Speck CL, Gallagher M, 2015. Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance. Neuroimage Clin 7, 688–698. [DOI] [PMC free article] [PubMed] [Google Scholar]
Bakker A, Krauss GL, Albert MS, Speck CL, Jones LR, Stark CE, Yassa MA, Bassett SS, Shelton AL, Gallagher M, 2012. Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron 74, 467–474. [DOI] [PMC free article] [PubMed] [Google Scholar]
Bejjani F, Evanno E, Zibara K, Piechaczyk M, Jariel-Encontre I, 2019. The AP-1 transcriptional complex: Local switch or remote command? Biochim Biophys Acta Rev Cancer 1872, 11–23. [DOI] [PubMed] [Google Scholar]
Benjamini Y, Hochberg Y, 1995. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society. Series B (Methodological) 57, 289–300. [Google Scholar]
Berdugo-Vega G, Arias-Gil G, Lopez-Fernandez A, Artegiani B, Wasielewska JM, Lee CC, Lippert MT, Kempermann G, Takagaki K, Calegari F, 2020. Increasing neurogenesis refines hippocampal activity rejuvenating navigational learning strategies and contextual memory throughout life. Nat Commun 11, 135. [DOI] [PMC free article] [PubMed] [Google Scholar]
Bernard C, 2016. The Diathesis-Epilepsy Model: How Past Events Impact the Development of Epilepsy and Comorbidities. Cold Spring Harb Perspect Med 6, a022418. [DOI] [PMC free article] [PubMed] [Google Scholar]
Berton O, Covington HE 3rd, Ebner K, Tsankova NM, Carle TL, Ulery P, Bhonsle A, Barrot M, Krishnan V, Singewald GM, Singewald N, Birnbaum S, Neve RL, Nestler EJ, 2007. Induction of deltaFosB in the periaqueductal gray by stress promotes active coping responses. Neuron 55, 289–300. [DOI] [PubMed] [Google Scholar]
Biddie SC, John S, Sabo PJ, Thurman RE, Johnson TA, Schiltz RL, Miranda TB, Sung MH, Trump S, Lightman SL, Vinson C, Stamatoyannopoulos JA, Hager GL, 2011. Transcription factor AP1 potentiates chromatin accessibility and glucocorticoid receptor binding. Mol Cell 43, 145–155. [DOI] [PMC free article] [PubMed] [Google Scholar]
Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A, Fridman WH, Pages F, Trajanoski Z, Galon J, 2009. ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics 25, 1091–1093. [DOI] [PMC free article] [PubMed] [Google Scholar]
Blumcke I, Beck H, Lie AA, Wiestler OD, 1999. Molecular neuropathology of human mesial temporal lobe epilepsy. Epilepsy Res 36, 205–223. [DOI] [PubMed] [Google Scholar]
Born HA, 2015. Seizures in Alzheimer’s disease. Neuroscience 286, 251–263. [DOI] [PubMed] [Google Scholar]
Braunewell KH, 2012. The visinin-like proteins VILIP-1 and VILIP-3 in Alzheimer’s disease-old wine in new bottles. Front Mol Neurosci 5, 20. [DOI] [PMC free article] [PubMed] [Google Scholar]
Brown PH, Kim SH, Wise SC, Sabichi AL, Birrer MJ, 1996. Dominant-negative mutants of cJun inhibit AP-1 activity through multiple mechanisms and with different potencies. Cell Growth Differ 7, 1013–1021. [PubMed] [Google Scholar]
Chauviere L, 2020. Potential causes of cognitive alterations in temporal lobe epilepsy. Behav Brain Res 378, 112310. [DOI] [PubMed] [Google Scholar]
Chen J, Nye HE, Kelz MB, Hiroi N, Nakabeppu Y, Hope BT, Nestler EJ, 1995. Regulation of DeltaFosB and FosB-like proteins by electroconvulsive seizure and cocaine treatments. Mol Pharmacol 48, 880–889. [PubMed] [Google Scholar]
Chen J, Zhang Y, Kelz MB, Steffen C, Ang ES, Zeng L, Nestler EJ, 2000. Induction of cyclin-dependent kinase 5 in the hippocampus by chronic electroconvulsive seizures: role of DeltaFosB. J Neurosci 20, 8965–8971. [DOI] [PMC free article] [PubMed] [Google Scholar]
Chen ZC, Zhang W, Chua LL, Chai C, Li R, Lin L, Cao Z, Angeles DC, Stanton LW, Peng JH, Zhou ZD, Lim KL, Zeng L, Tan EK, 2017. Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD activity and neurotoxicity in Parkinson’s disease. Sci Signal 10, eaam6790. [DOI] [PubMed] [Google Scholar]
Chin J 2011. Selecting a Mouse Model of Alzheimer’s Disease. In: Alzheimer’s Disease and Frontotemporal Dementia: Methods and Protocols. pp. 169–189. Ed. Roberson ED Humana Press: Totowa, NJ. [Google Scholar]
Chin J, Palop JJ, Puolivali J, Massaro C, Bien-Ly N, Gerstein H, Scearce-Levie K, Masliah E, Mucke L, 2005. Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer’s disease. J Neurosci 25, 9694–9703. [DOI] [PMC free article] [PubMed] [Google Scholar]
Chin J, Scharfman HE, 2013. Shared cognitive and behavioral impairments in epilepsy and Alzheimer’s disease and potential underlying mechanisms. Epilepsy Behav 26, 343–351. [DOI] [PMC free article] [PubMed] [Google Scholar]
Cho KO, Lybrand ZR, Ito N, Brulet R, Tafacory F, Zhang L, Good L, Ure K, Kernie SG, Birnbaum SG, Scharfman HE, Eisch AJ, Hsieh J, 2015. Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline. Nat Commun 6, 6606. [DOI] [PMC free article] [PubMed] [Google Scholar]
Cho S, Park EM, Kim Y, Liu N, Gal J, Volpe BT, Joh TH, 2001. Early c-Fos induction after cerebral ischemia: a possible neuroprotective role. J Cereb Blood Flow Metab 21, 550–556. [DOI] [PubMed] [Google Scholar]
Choi SH, Bylykbashi E, Chatila ZK, Lee SW, Pulli B, Clemenson GD, Kim E, Rompala A, Oram MK, Asselin C, Aronson J, Zhang C, Miller SJ, Lesinski A, Chen JW, Kim DY, van Praag H, Spiegelman BM, Gage FH, Tanzi RE, 2018. Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model. Science 361, eaan8821. [DOI] [PMC free article] [PubMed] [Google Scholar]
Clasadonte J, Deprez T, Stephens GS, Mairet-Coello G, Cortin PY, Boutier M, Frey A, Chin J, Rajman M, 2023. DeltaFosB is part of a homeostatic mechanism that protects the epileptic brain from further deterioration. Front. Mol. Neurosci. 16, 1324922. [DOI] [PMC free article] [PubMed] [Google Scholar]
Corbett BF, You JC, Zhang X, Pyfer MS, Tosi U, Iascone DM, Petrof I, Hazra A, Fu CH, Stephens GS, Ashok AA, Aschmies S, Zhao L, Nestler EJ, Chin J, 2017. DeltaFosB Regulates Gene Expression and Cognitive Dysfunction in a Mouse Model of Alzheimer’s Disease. Cell Rep 20, 344–355. [DOI] [PMC free article] [PubMed] [Google Scholar]
Coulter DA, 1999. Chronic epileptogenic cellular alterations in the limbic system after status epilepticus. Epilepsia 40 Suppl 1, S23–33; discussion S40–21. [DOI] [PubMed] [Google Scholar]
Coulter DA, Carlson GC 2007. Functional regulation of the dentate gyrus by GABA-mediated inhibition. In: Progress in Brain Research. pp. 235–812. Ed. Scharfman HE Elsevier. [DOI] [PubMed] [Google Scholar]
Eagle AL, Williams ES, Beatty JA, Cox CL, Robison AJ, 2018. DeltaFosB Decreases Excitability of Dorsal Hippocampal CA1 Neurons. eNeuro 5, ENEURO.0104–0118.2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
Fernandez-Albert J, Lipinski M, Lopez-Cascales MT, Rowley MJ, Martin-Gonzalez AM, Del Blanco B, Corces VG, Barco A, 2019. Immediate and deferred epigenomic signatures of in vivo neuronal activation in mouse hippocampus. Nat Neurosci 22, 1718–1730. [DOI] [PMC free article] [PubMed] [Google Scholar]
Flavahan WA, Gaskell E, Bernstein BE, 2017. Epigenetic plasticity and the hallmarks of cancer. Science 357, eaal2380. [DOI] [PMC free article] [PubMed] [Google Scholar]
Fu CH, Iascone DM, Petrof I, Hazra A, Zhang X, Pyfer MS, Tosi U, Corbett BF, Cai J, Lee J, Park J, Iacovitti L, Scharfman HE, Enikolopov G, Chin J, 2019. Early Seizure Activity Accelerates Depletion of Hippocampal Neural Stem Cells and Impairs Spatial Discrimination in an Alzheimer’s Disease Model. Cell Rep 27, 3741–3751 e3744. [DOI] [PMC free article] [PubMed] [Google Scholar]
Gajewski PA, Turecki G, Robison AJ, 2016. Differential Expression of FosB Proteins and Potential Target Genes in Select Brain Regions of Addiction and Depression Patients. PLoS One 11, e0160355. [DOI] [PMC free article] [PubMed] [Google Scholar]
Giau VV, Bagyinszky E, Yang YS, Youn YC, An SSA, Kim SY, 2019. Genetic analyses of early-onset Alzheimer’s disease using next generation sequencing. Sci Rep 9, 8368. [DOI] [PMC free article] [PubMed] [Google Scholar]
Guipponi M, Chentouf A, Webling KE, Freimann K, Crespel A, Nobile C, Lemke JR, Hansen J, Dorn T, Lesca G, Ryvlin P, Hirsch E, Rudolf G, Rosenberg DS, Weber Y, Becker F, Helbig I, Muhle H, Salzmann A, Chaouch M, Oubaiche ML, Ziglio S, Gehrig C, Santoni F, Pizzato M, Langel U, Antonarakis SE, 2015. Galanin pathogenic mutations in temporal lobe epilepsy. Hum Mol Genet 24, 3082–3091. [DOI] [PubMed] [Google Scholar]
Gurdon JB, Javed K, Vodnala M, Garrett N, 2020. Long-term association of a transcription factor with its chromatin binding site can stabilize gene expression and cell fate commitment. Proc Natl Acad Sci U S A 117, 15075–15084. [DOI] [PMC free article] [PubMed] [Google Scholar]
Hall AM, Throesch BT, Buckingham SC, Markwardt SJ, Peng Y, Wang Q, Hoffman DA, Roberson ED, 2015. Tau-Dependent Kv4.2 Depletion and Dendritic Hyperexcitability in a Mouse Model of Alzheimer’s Disease. The Journal of Neuroscience 35, 6221. [DOI] [PMC free article] [PubMed] [Google Scholar]
Hanke JM, Schindler KA, Seiler A, 2022. On the relationships between epilepsy, sleep, and Alzheimer’s disease: A narrative review. Epilepsy Behav 129, 108609. [DOI] [PubMed] [Google Scholar]
Harris SS, Wolf F, De Strooper B, Busche MA, 2020. Tipping the Scales: Peptide-Dependent Dysregulation of Neural Circuit Dynamics in Alzheimer’s Disease. Neuron 107, 417–435. [DOI] [PubMed] [Google Scholar]
Heinemann U, Beck H, Dreier JP, Ficker E, Stabel J, Zhang CL, 1992. The dentate gyrus as a regulated gate for the propagation of epileptiform activity. Epilepsy Res Suppl 7, 273–280. [PubMed] [Google Scholar]
Henshall DC, Kobow K, 2015. Epigenetics and Epilepsy. Cold Spring Harb Perspect Med 5. [DOI] [PMC free article] [PubMed] [Google Scholar]
Hiroi N, Marek GJ, Brown JR, Ye H, Saudou F, Vaidya VA, Duman RS, Greenberg ME, Nestler EJ, 1998. Essential role of the fosB gene in molecular, cellular, and behavioral actions of chronic electroconvulsive seizures. J Neurosci 18, 6952–6962. [DOI] [PMC free article] [PubMed] [Google Scholar]
Holmes GL, 2015. Cognitive impairment in epilepsy: the role of network abnormalities. Epileptic Disord 17, 101–116. [DOI] [PMC free article] [PubMed] [Google Scholar]
Hope BT, Kelz MB, Duman RS, Nestler EJ, 1994a. Chronic electroconvulsive seizure (ECS) treatment results in expression of a long-lasting AP-1 complex in brain with altered composition and characteristics. J Neurosci 14, 4318–4328. [DOI] [PMC free article] [PubMed] [Google Scholar]
Hope BT, Nye HE, Kelz MB, Self DW, Iadarola MJ, Nakabeppu Y, Duman RS, Nestler EJ, 1994b. Induction of a long-lasting AP-1 complex composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments. Neuron 13, 1235–1244. [DOI] [PubMed] [Google Scholar]
Ikrar T, Guo N, He K, Besnard A, Levinson S, Hill A, Lee HK, Hen R, Xu X, Sahay A, 2013. Adult neurogenesis modifies excitability of the dentate gyrus. Front Neural Circuits 7, 204. [DOI] [PMC free article] [PubMed] [Google Scholar]
Iwafuchi-Doi M, 2019. The mechanistic basis for chromatin regulation by pioneer transcription factors. Wiley Interdiscip Rev Syst Biol Med 11, e1427. [DOI] [PMC free article] [PubMed] [Google Scholar]
Jack CR Jr., Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, Shaw LM, Vemuri P, Wiste HJ, Weigand SD, Lesnick TG, Pankratz VS, Donohue MC, Trojanowski JQ, 2013. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 12, 207–216. [DOI] [PMC free article] [PubMed] [Google Scholar]
Jagirdar R, Fu CH, Park J, Corbett BF, Seibt FM, Beierlein M, Chin J, 2021. Restoring activity in the thalamic reticular nucleus improves sleep architecture and reduces Aβ accumulation in mice. Sci Transl Med 13, eabh4284. [DOI] [PMC free article] [PubMed] [Google Scholar]
Jain S, LaFrancois JJ, Botterill JJ, Alcantara-Gonzalez D, Scharfman HE, 2019. Adult neurogenesis in the mouse dentate gyrus protects the hippocampus from neuronal injury following severe seizures. Hippocampus 29, 683–709. [DOI] [PMC free article] [PubMed] [Google Scholar]
Johnson ECB, Ho K, Yu GQ, Das M, Sanchez PE, Djukic B, Lopez I, Yu X, Gill M, Zhang W, Paz JT, Palop JJ, Mucke L, 2020. Behavioral and neural network abnormalities in human APP transgenic mice resemble those of App knock-in mice and are modulated by familial Alzheimer’s disease mutations but not by inhibition of BACE1. Mol Neurodegener 15, 53. [DOI] [PMC free article] [PubMed] [Google Scholar]
Kadkhodaei B, Alvarsson A, Schintu N, Ramskold D, Volakakis N, Joodmardi E, Yoshitake T, Kehr J, Decressac M, Bjorklund A, Sandberg R, Svenningsson P, Perlmann T, 2013. Transcription factor Nurr1 maintains fiber integrity and nuclear-encoded mitochondrial gene expression in dopamine neurons. Proc Natl Acad Sci U S A 110, 2360–2365. [DOI] [PMC free article] [PubMed] [Google Scholar]
Kaech S, Banker G, 2006. Culturing hippocampal neurons. Nat Protoc 1, 2406–2415. [DOI] [PubMed] [Google Scholar]
Kam K, Duffy AM, Moretto J, LaFrancois JJ, Scharfman HE, 2016. Interictal spikes during sleep are an early defect in the Tg2576 mouse model of Aβ neuropathology. Sci Rep 6, 20119. [DOI] [PMC free article] [PubMed] [Google Scholar]
Kamondi A, Grigg-Damberger M, Loscher W, Tanila H, Horvath AA, 2024. Epilepsy and epileptiform activity in late-onset Alzheimer disease: clinical and pathophysiological advances, gaps and conundrums. Nat. Rev. Neurol. [DOI] [PubMed] [Google Scholar]
Kask K, Langel U, Bartfai T, 1995. Galanin--a neuropeptide with inhibitory actions. Cell Mol Neurobiol 15, 653–673. [DOI] [PMC free article] [PubMed] [Google Scholar]
Kesner RP, Taylor JO, Hoge J, Andy F, 2015. Role of the dentate gyrus in mediating object-spatial configuration recognition. Neurobiol Learn Mem 118, 42–48. [DOI] [PubMed] [Google Scholar]
Khan N, Schoenike B, Basu T, Grabenstatter H, Rodriguez G, Sindic C, Johnson M, Wallace E, Maganti R, Dingledine R, Roopra A, 2019. A systems approach identifies Enhancer of Zeste Homolog 2 (EZH2) as a protective factor in epilepsy. PLoS One 14, e0226733. [DOI] [PMC free article] [PubMed] [Google Scholar]
Kobow K, Blumcke I, 2018. Epigenetics in epilepsy. Neurosci Lett 667, 40–46. [DOI] [PubMed] [Google Scholar]
Krook-Magnuson E, Armstrong C, Bui A, Lew S, Oijala M, Soltesz I, 2015. In vivo evaluation of the dentate gate theory in epilepsy. J Physiol 593, 2379–2388. [DOI] [PMC free article] [PubMed] [Google Scholar]
Kurushima H, Ohno M, Miura T, Nakamura TY, Horie H, Kadoya T, Ooboshi H, Kitazono T, Ibayashi S, Iida M, Nakabeppu Y, 2005. Selective induction of DeltaFosB in the brain after transient forebrain ischemia accompanied by an increased expression of galectin-1, and the implication of DeltaFosB and galectin-1 in neuroprotection and neurogenesis. Cell Death Differ 12, 1078–1096. [DOI] [PubMed] [Google Scholar]
Lam AD, Deck G, Goldman A, Eskandar EN, Noebels J, Cole AJ, 2017. Silent hippocampal seizures and spikes identified by foramen ovale electrodes in Alzheimer’s disease. Nat Med 23, 678–680. [DOI] [PMC free article] [PubMed] [Google Scholar]
Lam AD, Noebels J, 2020. Night Watch on the Titanic: Detecting Early Signs of Epileptogenesis in Alzheimer Disease. Epilepsy Curr 20, 369–374. [DOI] [PMC free article] [PubMed] [Google Scholar]
Lam AD, Sarkis RA, Pellerin KR, Jing J, Dworetzky BA, Hoch DB, Jacobs CS, Lee JW, Weisholtz DS, Zepeda R, Westover MB, Cole AJ, Cash SS, 2020. Association of epileptiform abnormalities and seizures in Alzheimer disease. Neurology 95, e2259–e2270. [DOI] [PMC free article] [PubMed] [Google Scholar]
Li HL, Lu SJ, Sun YM, Guo QH, Sadovnick AD, Wu ZY, 2013. The LRRK2 R1628P variant plays a protective role in Han Chinese population with Alzheimer’s disease. CNS Neurosci Ther 19, 207–215. [DOI] [PMC free article] [PubMed] [Google Scholar]
Li P, Fu X, Smith NA, Ziobro J, Curiel J, Tenga MJ, Martin B, Freedman S, Cea-Del Rio CA, Oboti L, Tsuchida TN, Oluigbo C, Yaun A, Magge SN, O’Neill B, Kao A, Zelleke TG, Depositario-Cabacar DT, Ghimbovschi S, Knoblach S, Ho CY, Corbin JG, Goodkin HP, Vicini S, Huntsman MM, Gaillard WD, Valdez G, Liu JS, 2017. Loss of CLOCK Results in Dysfunction of Brain Circuits Underlying Focal Epilepsy. Neuron 96, 387–401 e386. [DOI] [PMC free article] [PubMed] [Google Scholar]
Liu Y, Cheng A, Li YJ, Yang Y, Kishimoto Y, Zhang S, Wang Y, Wan R, Raefsky SM, Lu D, Saito T, Saido T, Zhu J, Wu LJ, Mattson MP, 2019. SIRT3 mediates hippocampal synaptic adaptations to intermittent fasting and ameliorates deficits in APP mutant mice. Nat.Commun. 10, 1886. [DOI] [PMC free article] [PubMed] [Google Scholar]
Lothman EW, Stringer JL, Bertram EH, 1992. The dentate gyrus as a control point for seizures in the hippocampus and beyond. Epilepsy Res Suppl 7, 301–313. [PubMed] [Google Scholar]
Ma T, Trinh MA, Wexler AJ, Bourbon C, Gatti E, Pierre P, Cavener DR, Klann E, 2013. Suppression of eIF2alpha kinases alleviates Alzheimer’s disease-related plasticity and memory deficits. Nat Neurosci 16, 1299–1305. [DOI] [PMC free article] [PubMed] [Google Scholar]
Magloczky Z, Halasz P, Vajda J, Czirjak S, Freund TF, 1997. Loss of Calbindin-D28K immunoreactivity from dentate granule cells in human temporal lobe epilepsy. Neuroscience 76, 377–385. [DOI] [PubMed] [Google Scholar]
Malik AN, Vierbuchen T, Hemberg M, Rubin AA, Ling E, Couch CH, Stroud H, Spiegel I, Farh KK, Harmin DA, Greenberg ME, 2014. Genome-wide identification and characterization of functional neuronal activity-dependent enhancers. Nat Neurosci 17, 1330–1339. [DOI] [PMC free article] [PubMed] [Google Scholar]
Manning CE, Eagle AL, Kwiatkowski CC, Achargui R, Woodworth H, Potter E, Ohnishi Y, Leinninger GM, Robison AJ, 2019. Hippocampal Subgranular Zone FosB Expression Is Critical for Neurogenesis and Learning. Neuroscience 406, 225–233. [DOI] [PMC free article] [PubMed] [Google Scholar]
Matsuo M, Maeda T, Ishii K, Tajima D, Koga M, Hamasaki Y, 2011. Characterization of childhood-onset complex partial seizures associated with autism spectrum disorder. Epilepsy Behav 20, 524–527. [DOI] [PubMed] [Google Scholar]
Mazarati AM, 2004. Galanin and galanin receptors in epilepsy. Neuropeptides 38, 331–343. [DOI] [PubMed] [Google Scholar]
Mazarati AM, Liu H, Soomets U, Sankar R, Shin D, Katsumori H, Langel U, Wasterlain CG, 1998. Galanin modulation of seizures and seizure modulation of hippocampal galanin in animal models of status epilepticus. J Neurosci 18, 10070–10077. [DOI] [PMC free article] [PubMed] [Google Scholar]
McClelland S, Brennan GP, Dube C, Rajpara S, Iyer S, Richichi C, Bernard C, Baram TZ, 2014. The transcription factor NRSF contributes to epileptogenesis by selective repression of a subset of target genes. Elife 3, e01267. [DOI] [PMC free article] [PubMed] [Google Scholar]
McHugh SB, Lopes-Dos-Santos V, Gava GP, Hartwich K, Tam SKE, Bannerman DM, Dupret D, 2022. Adult-born dentate granule cells promote hippocampal population sparsity. Nat Neurosci 25, 1481–1491. [DOI] [PMC free article] [PubMed] [Google Scholar]
Meldrum BS, 1993. Excitotoxicity and selective neuronal loss in epilepsy. Brain Pathol 3, 405–412. [DOI] [PubMed] [Google Scholar]
Minkeviciene R, Rheims S, Dobszay MB, Zilberter M, Hartikainen J, Fulop L, Penke B, Zilberter Y, Harkany T, Pitkanen A, Tanila H, 2009. Amyloid beta-induced neuronal hyperexcitability triggers progressive epilepsy. J. Neurosci. 29, 3453–3462. [DOI] [PMC free article] [PubMed] [Google Scholar]
Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, Hu K, Kholodenko D, Johnson-Wood K, McConlogue L, 2000. High-level neuronal expression of Aβ1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 20, 4050–4058. [DOI] [PMC free article] [PubMed] [Google Scholar]
Nagerl UV, Mody I, Jeub M, Lie AA, Elger CE, Beck H, 2000. Surviving granule cells of the sclerotic human hippocampus have reduced Ca(2+) influx because of a loss of calbindin-D(28k) in temporal lobe epilepsy. J Neurosci 20, 1831–1836. [DOI] [PMC free article] [PubMed] [Google Scholar]
Neve RL, Neve KA, Nestler EJ, Carlezon WA Jr., 2005. Use of herpes virus amplicon vectors to study brain disorders. Biotechniques 39, 381–391. [DOI] [PubMed] [Google Scholar]
Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, Yoo J, Ho KO, Yu GQ, Kreitzer A, Finkbeiner S, Noebels JL, Mucke L, 2007. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron 55, 697–711. [DOI] [PMC free article] [PubMed] [Google Scholar]
Palop JJ, Jones B, Kekonius L, Chin J, Yu G-Q, Raber J, Masliah E, Mucke L, 2003. Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer’s disease-related cognitive deficits. Proceedings of the National Academy of Sciences 100, 9572–9577. [DOI] [PMC free article] [PubMed] [Google Scholar]
Palop JJ, Mucke L, 2009. Epilepsy and cognitive impairments in Alzheimer disease. Arch Neurol 66, 435–440. [DOI] [PMC free article] [PubMed] [Google Scholar]
R-Core-Team (2021) R: A Language and environment for statistical computing. R Foundation for Statistical Computing. [Google Scholar]
Ranasinghe KG, Kudo K, Hinkley L, Beagle A, Lerner H, Mizuiri D, Findlay A, Miller BL, Kramer JH, Gorno-Tempini ML, Rabinovici GD, Rankin KP, Garcia PA, Kirsch HE, Vossel K, Nagarajan SS, 2022. Neuronal synchrony abnormalities associated with subclinical epileptiform activity in early-onset Alzheimer’s disease. Brain 145, 744–753. [DOI] [PMC free article] [PubMed] [Google Scholar]
Rawat V, Goux W, Piechaczyk M, SR DM, 2016. c-Fos Protects Neurons Through a Noncanonical Mechanism Involving HDAC3 Interaction: Identification of a 21-Amino Acid Fragment with Neuroprotective Activity. Mol Neurobiol 53, 1165–1180. [DOI] [PMC free article] [PubMed] [Google Scholar]
Renthal W, Carle TL, Maze I, Covington HE 3rd, Truong HT, Alibhai I, Kumar A, Montgomery RL, Olson EN, Nestler EJ, 2008. DeltaFosB mediates epigenetic desensitization of the c-fos gene after chronic amphetamine exposure. J Neurosci 28, 7344–7349. [DOI] [PMC free article] [PubMed] [Google Scholar]
Reyes A, Kaestner E, Edmonds EC, Christina Macari A, Wang ZI, Drane DL, Punia V, Busch RM, Hermann BP, McDonald CR, Alzheimer’s Disease Neuroimaging I, 2021. Diagnosing cognitive disorders in older adults with epilepsy. Epilepsia 62, 460–471. [DOI] [PMC free article] [PubMed] [Google Scholar]
Robison AJ, Nestler EJ, 2011. Transcriptional and epigenetic mechanisms of addiction. Nat Rev Neurosci 12, 623–637. [DOI] [PMC free article] [PubMed] [Google Scholar]
Robison AJ, Nestler EJ, 2022. DeltaFosB: A Potentially Druggable Master Orchestrator of Activity-Dependent Gene Expression. ACS Chem Neurosci 13, 296–307. [DOI] [PMC free article] [PubMed] [Google Scholar]
Roopra A, Dingledine R, Hsieh J, 2012. Epigenetics and epilepsy. Epilepsia 53 Suppl 9, 2–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, Devidze N, Ho K, Yu GQ, Palop JJ, Mucke L, 2012. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model. Proc Natl Acad Sci U S A 109, E2895–2903. [DOI] [PMC free article] [PubMed] [Google Scholar]
Schanzenbacher CT, Sambandan S, Langer JD, Schuman EM, 2016. Nascent Proteome Remodeling following Homeostatic Scaling at Hippocampal Synapses. Neuron 92, 358–371. [DOI] [PMC free article] [PubMed] [Google Scholar]
Scharfman HE, 2012. Alzheimer’s disease and epilepsy: insight from animal models. Future Neurol 7, 177–192. [DOI] [PMC free article] [PubMed] [Google Scholar]
Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chetelat G, Teunissen CE, Cummings J, van der Flier WM, 2021. Alzheimer’s disease. Lancet 397, 1577–1590. [DOI] [PMC free article] [PubMed] [Google Scholar]
Schneider CA, Rasband WS, Eliceiri KW, 2012. NIH Image to ImageJ: 25 years of image analysis. Nat Methods 9, 671–675. [DOI] [PMC free article] [PubMed] [Google Scholar]
Selvarajah A, Zulfiqar-Ali Q, Marques P, Rong M, Andrade DM, 2021. A systematic review of adults with Dravet syndrome. Seizure 87, 39–45. [DOI] [PubMed] [Google Scholar]
Sen A, Capelli V, Husain M, 2018. Cognition and dementia in older patients with epilepsy. Brain 141, 1592–1608. [DOI] [PMC free article] [PubMed] [Google Scholar]
Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T, 2003. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13, 2498–2504. [DOI] [PMC free article] [PubMed] [Google Scholar]
Stephens GS, Fu CH, St Romain CP, Zheng Y, Botterill JJ, Scharfman HE, Liu Y, Chin J, 2020. Genes Bound by DeltaFosB in Different Conditions With Recurrent Seizures Regulate Similar Neuronal Functions. Front Neurosci 14, 472. [DOI] [PMC free article] [PubMed] [Google Scholar]
Su Y, Shin J, Zhong C, Wang S, Roychowdhury P, Lim J, Kim D, Ming GL, Song H, 2017. Neuronal activity modifies the chromatin accessibility landscape in the adult brain. Nat Neurosci 20, 476–483. [DOI] [PMC free article] [PubMed] [Google Scholar]
Tarquinio DC, Hou W, Berg A, Kaufmann WE, Lane JB, Skinner SA, Motil KJ, Neul JL, Percy AK, Glaze DG, 2017. Longitudinal course of epilepsy in Rett syndrome and related disorders. Brain 140, 306–318. [DOI] [PMC free article] [PubMed] [Google Scholar]
Vierbuchen T, Ling E, Cowley CJ, Couch CH, Wang X, Harmin DA, Roberts CWM, Greenberg ME, 2017. AP-1 Transcription Factors and the BAF Complex Mediate Signal-Dependent Enhancer Selection. Mol Cell 68, 1067–1082 e1012. [DOI] [PMC free article] [PubMed] [Google Scholar]
Volicer L, Smith S, Volicer BJ, 1995. Effect of seizures on progression of dementia of the Alzheimer type. Dementia 6, 258–263. [DOI] [PubMed] [Google Scholar]
Vossel K, Ranasinghe KG, Beagle AJ, La A, Ah Pook K, Castro M, Mizuiri D, Honma SM, Venkateswaran N, Koestler M, Zhang W, Mucke L, Howell MJ, Possin KL, Kramer JH, Boxer AL, Miller BL, Nagarajan SS, Kirsch HE, 2021. Effect of Levetiracetam on Cognition in Patients With Alzheimer Disease With and Without Epileptiform Activity: A Randomized Clinical Trial. JAMA Neurol 78, 1345–1354. [DOI] [PMC free article] [PubMed] [Google Scholar]
Vossel KA, Beagle AJ, Rabinovici GD, Shu H, Lee SE, Naasan G, Hegde M, Cornes SB, Henry ML, Nelson AB, Seeley WW, Geschwind MD, Gorno-Tempini ML, Shih T, Kirsch HE, Garcia PA, Miller BL, Mucke L, 2013. Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol 70, 1158–1166. [DOI] [PMC free article] [PubMed] [Google Scholar]
Vossel KA, Ranasinghe KG, Beagle AJ, Mizuiri D, Honma SM, Dowling AF, Darwish SM, Van Berlo V, Barnes DE, Mantle M, Karydas AM, Coppola G, Roberson ED, Miller BL, Garcia PA, Kirsch HE, Mucke L, Nagarajan SS, 2016. Incidence and impact of subclinical epileptiform activity in Alzheimer’s disease. Ann Neurol 80, 858–870. [DOI] [PMC free article] [PubMed] [Google Scholar]
Vossel KA, Tartaglia MC, Nygaard HB, Zeman AZ, Miller BL, 2017. Epileptic activity in Alzheimer’s disease: causes and clinical relevance. Lancet Neurol 16, 311–322. [DOI] [PMC free article] [PubMed] [Google Scholar]
Wang G, Zhang DF, Jiang HY, Fan Y, Ma L, Shen Z, Bi R, Xu M, Tan L, Shan B, Yao YG, Feng T, 2019. Mutation and association analyses of dementia-causal genes in Han Chinese patients with early-onset and familial Alzheimer’s disease. J Psychiatr Res 113, 141–147. [DOI] [PubMed] [Google Scholar]
Wang J, Lin ZJ, Liu L, Xu HQ, Shi YW, Yi YH, He N, Liao WP, 2017. Epilepsy-associated genes. Seizure 44, 11–20. [DOI] [PubMed] [Google Scholar]
Wang YY, Smith P, Murphy M, Cook M, 2010. Global expression profiling in epileptogenesis: does it add to the confusion? Brain Pathol 20, 1–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
Winstanley CA, LaPlant Q, Theobald DE, Green TA, Bachtell RK, Perrotti LI, DiLeone RJ, Russo SJ, Garth WJ, Self DW, Nestler EJ, 2007. DeltaFosB induction in orbitofrontal cortex mediates tolerance to cocaine-induced cognitive dysfunction. J Neurosci 27, 10497–10507. [DOI] [PMC free article] [PubMed] [Google Scholar]
Wright AL, Zinn R, Hohensinn B, Konen LM, Beynon SB, Tan RP, Clark IA, Abdipranoto A, Vissel B, 2013. Neuroinflammation and neuronal loss precede Aβ plaque deposition in the hAPP-J20 mouse model of Alzheimer’s disease. PLoS One 8, e59586. [DOI] [PMC free article] [PubMed] [Google Scholar]
Yao AY, Halloran PJ, Ge Y, Singh N, Zhou J, Galske J, He W, Yan R, Hu X, 2023. Bace1 Deletion in the Adult Reverses Epileptiform Activity and Sleep-wake Disturbances in AD Mice. J. Neurosci. 43, 6197–6211. [DOI] [PMC free article] [PubMed] [Google Scholar]
Yeh SY, Estill M, Lardner CK, Browne CJ, Minier-Toribio A, Futamura R, Beach K, McManus CA, Xu SJ, Zhang S, Heller EA, Shen L, Nestler EJ, 2023. Cell Type-Specific Whole-Genome Landscape of DeltaFosB Binding in the Nucleus Accumbens After Chronic Cocaine Exposure. Biol Psychiatry. [DOI] [PMC free article] [PubMed] [Google Scholar]
You JC, Muralidharan K, Park JW, Petrof I, Pyfer MS, Corbett BF, LaFrancois JJ, Zheng Y, Zhang X, Mohila CA, Yoshor D, Rissman RA, Nestler EJ, Scharfman HE, Chin J, 2017. Epigenetic suppression of hippocampal calbindin-D28k by DeltaFosB drives seizure-related cognitive deficits. Nat Med 23, 1377–1383. [DOI] [PMC free article] [PubMed] [Google Scholar]
You JC, Stephens GS, Fu CH, Zhang X, Liu Y, Chin J, 2018. Genome-wide profiling reveals functional diversification of ΔFosB gene targets in the hippocampus of an Alzheimer’s disease mouse model. PLoS One 13, e0192508. [DOI] [PMC free article] [PubMed] [Google Scholar]
Yutsudo N, Kamada T, Kajitani K, Nomaru H, Katogi A, Ohnishi YH, Ohnishi YN, Takase K, Sakumi K, Shigeto H, Nakabeppu Y, 2013. fosB-null mice display impaired adult hippocampal neurogenesis and spontaneous epilepsy with depressive behavior. Neuropsychopharmacology 38, 895–906. [DOI] [PMC free article] [PubMed] [Google Scholar]
Zachariou V, Bolanos CA, Selley DE, Theobald D, Cassidy MP, Kelz MB, Shaw-Lutchman T, Berton O, Sim-Selley LJ, Dileone RJ, Kumar A, Nestler EJ, 2006. An essential role for DeltaFosB in the nucleus accumbens in morphine action. Nat Neurosci 9, 205–211. [DOI] [PubMed] [Google Scholar]
Zhao Y, Ho P, Yih Y, Chen C, Lee WL, Tan EK, 2011. LRRK2 variant associated with Alzheimer’s disease. Neurobiol Aging 32, 1990–1993. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Stephens et al 2024 Figures Suppl

NIHMS2018836-supplement-Stephens_et_al_2024_Figures_Suppl.pdf^{(3.7MB, pdf)}

Suppl File 1

NIHMS2018836-supplement-Suppl_File_1.xls^{(60.5KB, xls)}

[R1] Aasly JO, Shi M, Sossi V, Stewart T, Johansen KK, Wszolek ZK, Uitti RJ, Hasegawa K, Yokoyama T, Zabetian CP, Kim HM, Leverenz JB, Ginghina C, Armaly J, Edwards KL, Snapinn KW, Stoessl AJ, Zhang J, 2012. Cerebrospinal fluid amyloid beta and tau in LRRK2 mutation carriers. Neurology 78, 55–61. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R2] Adlaf EW, Vaden RJ, Niver AJ, Manuel AF, Onyilo VC, Araujo MT, Dieni CV, Vo HT, King GD, Wadiche JI, Overstreet-Wadiche L, 2017. Adult-born neurons modify excitatory synaptic transmission to existing neurons. Elife 6, e19886. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R3] Altuna M, Giménez S, Fortea J, 2021. Epilepsy in Down Syndrome: A Highly Prevalent Comorbidity. J Clin Med 10, 2776. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R4] Amatniek JC, Hauser WA, DelCastillo-Castaneda C, Jacobs DM, Marder K, Bell K, Albert M, Brandt J, Stern Y, 2006. Incidence and predictors of seizures in patients with Alzheimer’s disease. Epilepsia 47, 867–872. [DOI] [PubMed] [Google Scholar]

[R5] Anouar Y, Lee HW, Eiden LE, 1999. Both inducible and constitutive activator protein-1-like transcription factors are used for transcriptional activation of the galanin gene by different first and second messenger pathways. Mol Pharmacol 56, 162–169. [DOI] [PubMed] [Google Scholar]

[R6] Baets J, Duan X, Wu Y, Smith G, Seeley WW, Mademan I, McGrath NM, Beadell NC, Khoury J, Botuyan MV, Mer G, Worrell GA, Hojo K, DeLeon J, Laura M, Liu YT, Senderek J, Weis J, Van den Bergh P, Merrill SL, Reilly MM, Houlden H, Grossman M, Scherer SS, De Jonghe P, Dyck PJ, Klein CJ, 2015. Defects of mutant DNMT1 are linked to a spectrum of neurological disorders. Brain 138, 845–861. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R7] Bakker A, Albert MS, Krauss G, Speck CL, Gallagher M, 2015. Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance. Neuroimage Clin 7, 688–698. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R8] Bakker A, Krauss GL, Albert MS, Speck CL, Jones LR, Stark CE, Yassa MA, Bassett SS, Shelton AL, Gallagher M, 2012. Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron 74, 467–474. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R9] Bejjani F, Evanno E, Zibara K, Piechaczyk M, Jariel-Encontre I, 2019. The AP-1 transcriptional complex: Local switch or remote command? Biochim Biophys Acta Rev Cancer 1872, 11–23. [DOI] [PubMed] [Google Scholar]

[R10] Benjamini Y, Hochberg Y, 1995. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society. Series B (Methodological) 57, 289–300. [Google Scholar]

[R11] Berdugo-Vega G, Arias-Gil G, Lopez-Fernandez A, Artegiani B, Wasielewska JM, Lee CC, Lippert MT, Kempermann G, Takagaki K, Calegari F, 2020. Increasing neurogenesis refines hippocampal activity rejuvenating navigational learning strategies and contextual memory throughout life. Nat Commun 11, 135. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R12] Bernard C, 2016. The Diathesis-Epilepsy Model: How Past Events Impact the Development of Epilepsy and Comorbidities. Cold Spring Harb Perspect Med 6, a022418. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R13] Berton O, Covington HE 3rd, Ebner K, Tsankova NM, Carle TL, Ulery P, Bhonsle A, Barrot M, Krishnan V, Singewald GM, Singewald N, Birnbaum S, Neve RL, Nestler EJ, 2007. Induction of deltaFosB in the periaqueductal gray by stress promotes active coping responses. Neuron 55, 289–300. [DOI] [PubMed] [Google Scholar]

[R14] Biddie SC, John S, Sabo PJ, Thurman RE, Johnson TA, Schiltz RL, Miranda TB, Sung MH, Trump S, Lightman SL, Vinson C, Stamatoyannopoulos JA, Hager GL, 2011. Transcription factor AP1 potentiates chromatin accessibility and glucocorticoid receptor binding. Mol Cell 43, 145–155. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R15] Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A, Fridman WH, Pages F, Trajanoski Z, Galon J, 2009. ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics 25, 1091–1093. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R16] Blumcke I, Beck H, Lie AA, Wiestler OD, 1999. Molecular neuropathology of human mesial temporal lobe epilepsy. Epilepsy Res 36, 205–223. [DOI] [PubMed] [Google Scholar]

[R17] Born HA, 2015. Seizures in Alzheimer’s disease. Neuroscience 286, 251–263. [DOI] [PubMed] [Google Scholar]

[R18] Braunewell KH, 2012. The visinin-like proteins VILIP-1 and VILIP-3 in Alzheimer’s disease-old wine in new bottles. Front Mol Neurosci 5, 20. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R19] Brown PH, Kim SH, Wise SC, Sabichi AL, Birrer MJ, 1996. Dominant-negative mutants of cJun inhibit AP-1 activity through multiple mechanisms and with different potencies. Cell Growth Differ 7, 1013–1021. [PubMed] [Google Scholar]

[R20] Chauviere L, 2020. Potential causes of cognitive alterations in temporal lobe epilepsy. Behav Brain Res 378, 112310. [DOI] [PubMed] [Google Scholar]

[R21] Chen J, Nye HE, Kelz MB, Hiroi N, Nakabeppu Y, Hope BT, Nestler EJ, 1995. Regulation of DeltaFosB and FosB-like proteins by electroconvulsive seizure and cocaine treatments. Mol Pharmacol 48, 880–889. [PubMed] [Google Scholar]

[R22] Chen J, Zhang Y, Kelz MB, Steffen C, Ang ES, Zeng L, Nestler EJ, 2000. Induction of cyclin-dependent kinase 5 in the hippocampus by chronic electroconvulsive seizures: role of DeltaFosB. J Neurosci 20, 8965–8971. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R23] Chen ZC, Zhang W, Chua LL, Chai C, Li R, Lin L, Cao Z, Angeles DC, Stanton LW, Peng JH, Zhou ZD, Lim KL, Zeng L, Tan EK, 2017. Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD activity and neurotoxicity in Parkinson’s disease. Sci Signal 10, eaam6790. [DOI] [PubMed] [Google Scholar]

[R24] Chin J 2011. Selecting a Mouse Model of Alzheimer’s Disease. In: Alzheimer’s Disease and Frontotemporal Dementia: Methods and Protocols. pp. 169–189. Ed. Roberson ED Humana Press: Totowa, NJ. [Google Scholar]

[R25] Chin J, Palop JJ, Puolivali J, Massaro C, Bien-Ly N, Gerstein H, Scearce-Levie K, Masliah E, Mucke L, 2005. Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer’s disease. J Neurosci 25, 9694–9703. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R26] Chin J, Scharfman HE, 2013. Shared cognitive and behavioral impairments in epilepsy and Alzheimer’s disease and potential underlying mechanisms. Epilepsy Behav 26, 343–351. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R27] Cho KO, Lybrand ZR, Ito N, Brulet R, Tafacory F, Zhang L, Good L, Ure K, Kernie SG, Birnbaum SG, Scharfman HE, Eisch AJ, Hsieh J, 2015. Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline. Nat Commun 6, 6606. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R28] Cho S, Park EM, Kim Y, Liu N, Gal J, Volpe BT, Joh TH, 2001. Early c-Fos induction after cerebral ischemia: a possible neuroprotective role. J Cereb Blood Flow Metab 21, 550–556. [DOI] [PubMed] [Google Scholar]

[R29] Choi SH, Bylykbashi E, Chatila ZK, Lee SW, Pulli B, Clemenson GD, Kim E, Rompala A, Oram MK, Asselin C, Aronson J, Zhang C, Miller SJ, Lesinski A, Chen JW, Kim DY, van Praag H, Spiegelman BM, Gage FH, Tanzi RE, 2018. Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model. Science 361, eaan8821. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R30] Clasadonte J, Deprez T, Stephens GS, Mairet-Coello G, Cortin PY, Boutier M, Frey A, Chin J, Rajman M, 2023. DeltaFosB is part of a homeostatic mechanism that protects the epileptic brain from further deterioration. Front. Mol. Neurosci. 16, 1324922. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R31] Corbett BF, You JC, Zhang X, Pyfer MS, Tosi U, Iascone DM, Petrof I, Hazra A, Fu CH, Stephens GS, Ashok AA, Aschmies S, Zhao L, Nestler EJ, Chin J, 2017. DeltaFosB Regulates Gene Expression and Cognitive Dysfunction in a Mouse Model of Alzheimer’s Disease. Cell Rep 20, 344–355. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R32] Coulter DA, 1999. Chronic epileptogenic cellular alterations in the limbic system after status epilepticus. Epilepsia 40 Suppl 1, S23–33; discussion S40–21. [DOI] [PubMed] [Google Scholar]

[R33] Coulter DA, Carlson GC 2007. Functional regulation of the dentate gyrus by GABA-mediated inhibition. In: Progress in Brain Research. pp. 235–812. Ed. Scharfman HE Elsevier. [DOI] [PubMed] [Google Scholar]

[R34] Eagle AL, Williams ES, Beatty JA, Cox CL, Robison AJ, 2018. DeltaFosB Decreases Excitability of Dorsal Hippocampal CA1 Neurons. eNeuro 5, ENEURO.0104–0118.2018. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R35] Fernandez-Albert J, Lipinski M, Lopez-Cascales MT, Rowley MJ, Martin-Gonzalez AM, Del Blanco B, Corces VG, Barco A, 2019. Immediate and deferred epigenomic signatures of in vivo neuronal activation in mouse hippocampus. Nat Neurosci 22, 1718–1730. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R36] Flavahan WA, Gaskell E, Bernstein BE, 2017. Epigenetic plasticity and the hallmarks of cancer. Science 357, eaal2380. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R37] Fu CH, Iascone DM, Petrof I, Hazra A, Zhang X, Pyfer MS, Tosi U, Corbett BF, Cai J, Lee J, Park J, Iacovitti L, Scharfman HE, Enikolopov G, Chin J, 2019. Early Seizure Activity Accelerates Depletion of Hippocampal Neural Stem Cells and Impairs Spatial Discrimination in an Alzheimer’s Disease Model. Cell Rep 27, 3741–3751 e3744. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R38] Gajewski PA, Turecki G, Robison AJ, 2016. Differential Expression of FosB Proteins and Potential Target Genes in Select Brain Regions of Addiction and Depression Patients. PLoS One 11, e0160355. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R39] Giau VV, Bagyinszky E, Yang YS, Youn YC, An SSA, Kim SY, 2019. Genetic analyses of early-onset Alzheimer’s disease using next generation sequencing. Sci Rep 9, 8368. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R40] Guipponi M, Chentouf A, Webling KE, Freimann K, Crespel A, Nobile C, Lemke JR, Hansen J, Dorn T, Lesca G, Ryvlin P, Hirsch E, Rudolf G, Rosenberg DS, Weber Y, Becker F, Helbig I, Muhle H, Salzmann A, Chaouch M, Oubaiche ML, Ziglio S, Gehrig C, Santoni F, Pizzato M, Langel U, Antonarakis SE, 2015. Galanin pathogenic mutations in temporal lobe epilepsy. Hum Mol Genet 24, 3082–3091. [DOI] [PubMed] [Google Scholar]

[R41] Gurdon JB, Javed K, Vodnala M, Garrett N, 2020. Long-term association of a transcription factor with its chromatin binding site can stabilize gene expression and cell fate commitment. Proc Natl Acad Sci U S A 117, 15075–15084. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R42] Hall AM, Throesch BT, Buckingham SC, Markwardt SJ, Peng Y, Wang Q, Hoffman DA, Roberson ED, 2015. Tau-Dependent Kv4.2 Depletion and Dendritic Hyperexcitability in a Mouse Model of Alzheimer’s Disease. The Journal of Neuroscience 35, 6221. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R43] Hanke JM, Schindler KA, Seiler A, 2022. On the relationships between epilepsy, sleep, and Alzheimer’s disease: A narrative review. Epilepsy Behav 129, 108609. [DOI] [PubMed] [Google Scholar]

[R44] Harris SS, Wolf F, De Strooper B, Busche MA, 2020. Tipping the Scales: Peptide-Dependent Dysregulation of Neural Circuit Dynamics in Alzheimer’s Disease. Neuron 107, 417–435. [DOI] [PubMed] [Google Scholar]

[R45] Heinemann U, Beck H, Dreier JP, Ficker E, Stabel J, Zhang CL, 1992. The dentate gyrus as a regulated gate for the propagation of epileptiform activity. Epilepsy Res Suppl 7, 273–280. [PubMed] [Google Scholar]

[R46] Henshall DC, Kobow K, 2015. Epigenetics and Epilepsy. Cold Spring Harb Perspect Med 5. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R47] Hiroi N, Marek GJ, Brown JR, Ye H, Saudou F, Vaidya VA, Duman RS, Greenberg ME, Nestler EJ, 1998. Essential role of the fosB gene in molecular, cellular, and behavioral actions of chronic electroconvulsive seizures. J Neurosci 18, 6952–6962. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R48] Holmes GL, 2015. Cognitive impairment in epilepsy: the role of network abnormalities. Epileptic Disord 17, 101–116. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R49] Hope BT, Kelz MB, Duman RS, Nestler EJ, 1994a. Chronic electroconvulsive seizure (ECS) treatment results in expression of a long-lasting AP-1 complex in brain with altered composition and characteristics. J Neurosci 14, 4318–4328. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R50] Hope BT, Nye HE, Kelz MB, Self DW, Iadarola MJ, Nakabeppu Y, Duman RS, Nestler EJ, 1994b. Induction of a long-lasting AP-1 complex composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments. Neuron 13, 1235–1244. [DOI] [PubMed] [Google Scholar]

[R51] Ikrar T, Guo N, He K, Besnard A, Levinson S, Hill A, Lee HK, Hen R, Xu X, Sahay A, 2013. Adult neurogenesis modifies excitability of the dentate gyrus. Front Neural Circuits 7, 204. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R52] Iwafuchi-Doi M, 2019. The mechanistic basis for chromatin regulation by pioneer transcription factors. Wiley Interdiscip Rev Syst Biol Med 11, e1427. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R53] Jack CR Jr., Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, Shaw LM, Vemuri P, Wiste HJ, Weigand SD, Lesnick TG, Pankratz VS, Donohue MC, Trojanowski JQ, 2013. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 12, 207–216. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R54] Jagirdar R, Fu CH, Park J, Corbett BF, Seibt FM, Beierlein M, Chin J, 2021. Restoring activity in the thalamic reticular nucleus improves sleep architecture and reduces Aβ accumulation in mice. Sci Transl Med 13, eabh4284. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R55] Jain S, LaFrancois JJ, Botterill JJ, Alcantara-Gonzalez D, Scharfman HE, 2019. Adult neurogenesis in the mouse dentate gyrus protects the hippocampus from neuronal injury following severe seizures. Hippocampus 29, 683–709. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R56] Johnson ECB, Ho K, Yu GQ, Das M, Sanchez PE, Djukic B, Lopez I, Yu X, Gill M, Zhang W, Paz JT, Palop JJ, Mucke L, 2020. Behavioral and neural network abnormalities in human APP transgenic mice resemble those of App knock-in mice and are modulated by familial Alzheimer’s disease mutations but not by inhibition of BACE1. Mol Neurodegener 15, 53. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R57] Kadkhodaei B, Alvarsson A, Schintu N, Ramskold D, Volakakis N, Joodmardi E, Yoshitake T, Kehr J, Decressac M, Bjorklund A, Sandberg R, Svenningsson P, Perlmann T, 2013. Transcription factor Nurr1 maintains fiber integrity and nuclear-encoded mitochondrial gene expression in dopamine neurons. Proc Natl Acad Sci U S A 110, 2360–2365. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R58] Kaech S, Banker G, 2006. Culturing hippocampal neurons. Nat Protoc 1, 2406–2415. [DOI] [PubMed] [Google Scholar]

[R59] Kam K, Duffy AM, Moretto J, LaFrancois JJ, Scharfman HE, 2016. Interictal spikes during sleep are an early defect in the Tg2576 mouse model of Aβ neuropathology. Sci Rep 6, 20119. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R60] Kamondi A, Grigg-Damberger M, Loscher W, Tanila H, Horvath AA, 2024. Epilepsy and epileptiform activity in late-onset Alzheimer disease: clinical and pathophysiological advances, gaps and conundrums. Nat. Rev. Neurol. [DOI] [PubMed] [Google Scholar]

[R61] Kask K, Langel U, Bartfai T, 1995. Galanin--a neuropeptide with inhibitory actions. Cell Mol Neurobiol 15, 653–673. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R62] Kesner RP, Taylor JO, Hoge J, Andy F, 2015. Role of the dentate gyrus in mediating object-spatial configuration recognition. Neurobiol Learn Mem 118, 42–48. [DOI] [PubMed] [Google Scholar]

[R63] Khan N, Schoenike B, Basu T, Grabenstatter H, Rodriguez G, Sindic C, Johnson M, Wallace E, Maganti R, Dingledine R, Roopra A, 2019. A systems approach identifies Enhancer of Zeste Homolog 2 (EZH2) as a protective factor in epilepsy. PLoS One 14, e0226733. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R64] Kobow K, Blumcke I, 2018. Epigenetics in epilepsy. Neurosci Lett 667, 40–46. [DOI] [PubMed] [Google Scholar]

[R65] Krook-Magnuson E, Armstrong C, Bui A, Lew S, Oijala M, Soltesz I, 2015. In vivo evaluation of the dentate gate theory in epilepsy. J Physiol 593, 2379–2388. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R66] Kurushima H, Ohno M, Miura T, Nakamura TY, Horie H, Kadoya T, Ooboshi H, Kitazono T, Ibayashi S, Iida M, Nakabeppu Y, 2005. Selective induction of DeltaFosB in the brain after transient forebrain ischemia accompanied by an increased expression of galectin-1, and the implication of DeltaFosB and galectin-1 in neuroprotection and neurogenesis. Cell Death Differ 12, 1078–1096. [DOI] [PubMed] [Google Scholar]

[R67] Lam AD, Deck G, Goldman A, Eskandar EN, Noebels J, Cole AJ, 2017. Silent hippocampal seizures and spikes identified by foramen ovale electrodes in Alzheimer’s disease. Nat Med 23, 678–680. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R68] Lam AD, Noebels J, 2020. Night Watch on the Titanic: Detecting Early Signs of Epileptogenesis in Alzheimer Disease. Epilepsy Curr 20, 369–374. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R69] Lam AD, Sarkis RA, Pellerin KR, Jing J, Dworetzky BA, Hoch DB, Jacobs CS, Lee JW, Weisholtz DS, Zepeda R, Westover MB, Cole AJ, Cash SS, 2020. Association of epileptiform abnormalities and seizures in Alzheimer disease. Neurology 95, e2259–e2270. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R70] Li HL, Lu SJ, Sun YM, Guo QH, Sadovnick AD, Wu ZY, 2013. The LRRK2 R1628P variant plays a protective role in Han Chinese population with Alzheimer’s disease. CNS Neurosci Ther 19, 207–215. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R71] Li P, Fu X, Smith NA, Ziobro J, Curiel J, Tenga MJ, Martin B, Freedman S, Cea-Del Rio CA, Oboti L, Tsuchida TN, Oluigbo C, Yaun A, Magge SN, O’Neill B, Kao A, Zelleke TG, Depositario-Cabacar DT, Ghimbovschi S, Knoblach S, Ho CY, Corbin JG, Goodkin HP, Vicini S, Huntsman MM, Gaillard WD, Valdez G, Liu JS, 2017. Loss of CLOCK Results in Dysfunction of Brain Circuits Underlying Focal Epilepsy. Neuron 96, 387–401 e386. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R72] Liu Y, Cheng A, Li YJ, Yang Y, Kishimoto Y, Zhang S, Wang Y, Wan R, Raefsky SM, Lu D, Saito T, Saido T, Zhu J, Wu LJ, Mattson MP, 2019. SIRT3 mediates hippocampal synaptic adaptations to intermittent fasting and ameliorates deficits in APP mutant mice. Nat.Commun. 10, 1886. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R73] Lothman EW, Stringer JL, Bertram EH, 1992. The dentate gyrus as a control point for seizures in the hippocampus and beyond. Epilepsy Res Suppl 7, 301–313. [PubMed] [Google Scholar]

[R74] Ma T, Trinh MA, Wexler AJ, Bourbon C, Gatti E, Pierre P, Cavener DR, Klann E, 2013. Suppression of eIF2alpha kinases alleviates Alzheimer’s disease-related plasticity and memory deficits. Nat Neurosci 16, 1299–1305. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R75] Magloczky Z, Halasz P, Vajda J, Czirjak S, Freund TF, 1997. Loss of Calbindin-D28K immunoreactivity from dentate granule cells in human temporal lobe epilepsy. Neuroscience 76, 377–385. [DOI] [PubMed] [Google Scholar]

[R76] Malik AN, Vierbuchen T, Hemberg M, Rubin AA, Ling E, Couch CH, Stroud H, Spiegel I, Farh KK, Harmin DA, Greenberg ME, 2014. Genome-wide identification and characterization of functional neuronal activity-dependent enhancers. Nat Neurosci 17, 1330–1339. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R77] Manning CE, Eagle AL, Kwiatkowski CC, Achargui R, Woodworth H, Potter E, Ohnishi Y, Leinninger GM, Robison AJ, 2019. Hippocampal Subgranular Zone FosB Expression Is Critical for Neurogenesis and Learning. Neuroscience 406, 225–233. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R78] Matsuo M, Maeda T, Ishii K, Tajima D, Koga M, Hamasaki Y, 2011. Characterization of childhood-onset complex partial seizures associated with autism spectrum disorder. Epilepsy Behav 20, 524–527. [DOI] [PubMed] [Google Scholar]

[R79] Mazarati AM, 2004. Galanin and galanin receptors in epilepsy. Neuropeptides 38, 331–343. [DOI] [PubMed] [Google Scholar]

[R80] Mazarati AM, Liu H, Soomets U, Sankar R, Shin D, Katsumori H, Langel U, Wasterlain CG, 1998. Galanin modulation of seizures and seizure modulation of hippocampal galanin in animal models of status epilepticus. J Neurosci 18, 10070–10077. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R81] McClelland S, Brennan GP, Dube C, Rajpara S, Iyer S, Richichi C, Bernard C, Baram TZ, 2014. The transcription factor NRSF contributes to epileptogenesis by selective repression of a subset of target genes. Elife 3, e01267. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R82] McHugh SB, Lopes-Dos-Santos V, Gava GP, Hartwich K, Tam SKE, Bannerman DM, Dupret D, 2022. Adult-born dentate granule cells promote hippocampal population sparsity. Nat Neurosci 25, 1481–1491. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R83] Meldrum BS, 1993. Excitotoxicity and selective neuronal loss in epilepsy. Brain Pathol 3, 405–412. [DOI] [PubMed] [Google Scholar]

[R84] Minkeviciene R, Rheims S, Dobszay MB, Zilberter M, Hartikainen J, Fulop L, Penke B, Zilberter Y, Harkany T, Pitkanen A, Tanila H, 2009. Amyloid beta-induced neuronal hyperexcitability triggers progressive epilepsy. J. Neurosci. 29, 3453–3462. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R85] Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, Hu K, Kholodenko D, Johnson-Wood K, McConlogue L, 2000. High-level neuronal expression of Aβ1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 20, 4050–4058. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R86] Nagerl UV, Mody I, Jeub M, Lie AA, Elger CE, Beck H, 2000. Surviving granule cells of the sclerotic human hippocampus have reduced Ca(2+) influx because of a loss of calbindin-D(28k) in temporal lobe epilepsy. J Neurosci 20, 1831–1836. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R87] Neve RL, Neve KA, Nestler EJ, Carlezon WA Jr., 2005. Use of herpes virus amplicon vectors to study brain disorders. Biotechniques 39, 381–391. [DOI] [PubMed] [Google Scholar]

[R88] Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, Yoo J, Ho KO, Yu GQ, Kreitzer A, Finkbeiner S, Noebels JL, Mucke L, 2007. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron 55, 697–711. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R89] Palop JJ, Jones B, Kekonius L, Chin J, Yu G-Q, Raber J, Masliah E, Mucke L, 2003. Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer’s disease-related cognitive deficits. Proceedings of the National Academy of Sciences 100, 9572–9577. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R90] Palop JJ, Mucke L, 2009. Epilepsy and cognitive impairments in Alzheimer disease. Arch Neurol 66, 435–440. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R91] R-Core-Team (2021) R: A Language and environment for statistical computing. R Foundation for Statistical Computing. [Google Scholar]

[R92] Ranasinghe KG, Kudo K, Hinkley L, Beagle A, Lerner H, Mizuiri D, Findlay A, Miller BL, Kramer JH, Gorno-Tempini ML, Rabinovici GD, Rankin KP, Garcia PA, Kirsch HE, Vossel K, Nagarajan SS, 2022. Neuronal synchrony abnormalities associated with subclinical epileptiform activity in early-onset Alzheimer’s disease. Brain 145, 744–753. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R93] Rawat V, Goux W, Piechaczyk M, SR DM, 2016. c-Fos Protects Neurons Through a Noncanonical Mechanism Involving HDAC3 Interaction: Identification of a 21-Amino Acid Fragment with Neuroprotective Activity. Mol Neurobiol 53, 1165–1180. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R94] Renthal W, Carle TL, Maze I, Covington HE 3rd, Truong HT, Alibhai I, Kumar A, Montgomery RL, Olson EN, Nestler EJ, 2008. DeltaFosB mediates epigenetic desensitization of the c-fos gene after chronic amphetamine exposure. J Neurosci 28, 7344–7349. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R95] Reyes A, Kaestner E, Edmonds EC, Christina Macari A, Wang ZI, Drane DL, Punia V, Busch RM, Hermann BP, McDonald CR, Alzheimer’s Disease Neuroimaging I, 2021. Diagnosing cognitive disorders in older adults with epilepsy. Epilepsia 62, 460–471. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R96] Robison AJ, Nestler EJ, 2011. Transcriptional and epigenetic mechanisms of addiction. Nat Rev Neurosci 12, 623–637. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R97] Robison AJ, Nestler EJ, 2022. DeltaFosB: A Potentially Druggable Master Orchestrator of Activity-Dependent Gene Expression. ACS Chem Neurosci 13, 296–307. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R98] Roopra A, Dingledine R, Hsieh J, 2012. Epigenetics and epilepsy. Epilepsia 53 Suppl 9, 2–10. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R99] Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, Devidze N, Ho K, Yu GQ, Palop JJ, Mucke L, 2012. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model. Proc Natl Acad Sci U S A 109, E2895–2903. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R100] Schanzenbacher CT, Sambandan S, Langer JD, Schuman EM, 2016. Nascent Proteome Remodeling following Homeostatic Scaling at Hippocampal Synapses. Neuron 92, 358–371. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R101] Scharfman HE, 2012. Alzheimer’s disease and epilepsy: insight from animal models. Future Neurol 7, 177–192. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R102] Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chetelat G, Teunissen CE, Cummings J, van der Flier WM, 2021. Alzheimer’s disease. Lancet 397, 1577–1590. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R103] Schneider CA, Rasband WS, Eliceiri KW, 2012. NIH Image to ImageJ: 25 years of image analysis. Nat Methods 9, 671–675. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R104] Selvarajah A, Zulfiqar-Ali Q, Marques P, Rong M, Andrade DM, 2021. A systematic review of adults with Dravet syndrome. Seizure 87, 39–45. [DOI] [PubMed] [Google Scholar]

[R105] Sen A, Capelli V, Husain M, 2018. Cognition and dementia in older patients with epilepsy. Brain 141, 1592–1608. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R106] Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T, 2003. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13, 2498–2504. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R107] Stephens GS, Fu CH, St Romain CP, Zheng Y, Botterill JJ, Scharfman HE, Liu Y, Chin J, 2020. Genes Bound by DeltaFosB in Different Conditions With Recurrent Seizures Regulate Similar Neuronal Functions. Front Neurosci 14, 472. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R108] Su Y, Shin J, Zhong C, Wang S, Roychowdhury P, Lim J, Kim D, Ming GL, Song H, 2017. Neuronal activity modifies the chromatin accessibility landscape in the adult brain. Nat Neurosci 20, 476–483. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R109] Tarquinio DC, Hou W, Berg A, Kaufmann WE, Lane JB, Skinner SA, Motil KJ, Neul JL, Percy AK, Glaze DG, 2017. Longitudinal course of epilepsy in Rett syndrome and related disorders. Brain 140, 306–318. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R110] Vierbuchen T, Ling E, Cowley CJ, Couch CH, Wang X, Harmin DA, Roberts CWM, Greenberg ME, 2017. AP-1 Transcription Factors and the BAF Complex Mediate Signal-Dependent Enhancer Selection. Mol Cell 68, 1067–1082 e1012. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R111] Volicer L, Smith S, Volicer BJ, 1995. Effect of seizures on progression of dementia of the Alzheimer type. Dementia 6, 258–263. [DOI] [PubMed] [Google Scholar]

[R112] Vossel K, Ranasinghe KG, Beagle AJ, La A, Ah Pook K, Castro M, Mizuiri D, Honma SM, Venkateswaran N, Koestler M, Zhang W, Mucke L, Howell MJ, Possin KL, Kramer JH, Boxer AL, Miller BL, Nagarajan SS, Kirsch HE, 2021. Effect of Levetiracetam on Cognition in Patients With Alzheimer Disease With and Without Epileptiform Activity: A Randomized Clinical Trial. JAMA Neurol 78, 1345–1354. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R113] Vossel KA, Beagle AJ, Rabinovici GD, Shu H, Lee SE, Naasan G, Hegde M, Cornes SB, Henry ML, Nelson AB, Seeley WW, Geschwind MD, Gorno-Tempini ML, Shih T, Kirsch HE, Garcia PA, Miller BL, Mucke L, 2013. Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol 70, 1158–1166. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R114] Vossel KA, Ranasinghe KG, Beagle AJ, Mizuiri D, Honma SM, Dowling AF, Darwish SM, Van Berlo V, Barnes DE, Mantle M, Karydas AM, Coppola G, Roberson ED, Miller BL, Garcia PA, Kirsch HE, Mucke L, Nagarajan SS, 2016. Incidence and impact of subclinical epileptiform activity in Alzheimer’s disease. Ann Neurol 80, 858–870. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R115] Vossel KA, Tartaglia MC, Nygaard HB, Zeman AZ, Miller BL, 2017. Epileptic activity in Alzheimer’s disease: causes and clinical relevance. Lancet Neurol 16, 311–322. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R116] Wang G, Zhang DF, Jiang HY, Fan Y, Ma L, Shen Z, Bi R, Xu M, Tan L, Shan B, Yao YG, Feng T, 2019. Mutation and association analyses of dementia-causal genes in Han Chinese patients with early-onset and familial Alzheimer’s disease. J Psychiatr Res 113, 141–147. [DOI] [PubMed] [Google Scholar]

[R117] Wang J, Lin ZJ, Liu L, Xu HQ, Shi YW, Yi YH, He N, Liao WP, 2017. Epilepsy-associated genes. Seizure 44, 11–20. [DOI] [PubMed] [Google Scholar]

[R118] Wang YY, Smith P, Murphy M, Cook M, 2010. Global expression profiling in epileptogenesis: does it add to the confusion? Brain Pathol 20, 1–16. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R119] Winstanley CA, LaPlant Q, Theobald DE, Green TA, Bachtell RK, Perrotti LI, DiLeone RJ, Russo SJ, Garth WJ, Self DW, Nestler EJ, 2007. DeltaFosB induction in orbitofrontal cortex mediates tolerance to cocaine-induced cognitive dysfunction. J Neurosci 27, 10497–10507. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R120] Wright AL, Zinn R, Hohensinn B, Konen LM, Beynon SB, Tan RP, Clark IA, Abdipranoto A, Vissel B, 2013. Neuroinflammation and neuronal loss precede Aβ plaque deposition in the hAPP-J20 mouse model of Alzheimer’s disease. PLoS One 8, e59586. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R121] Yao AY, Halloran PJ, Ge Y, Singh N, Zhou J, Galske J, He W, Yan R, Hu X, 2023. Bace1 Deletion in the Adult Reverses Epileptiform Activity and Sleep-wake Disturbances in AD Mice. J. Neurosci. 43, 6197–6211. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R122] Yeh SY, Estill M, Lardner CK, Browne CJ, Minier-Toribio A, Futamura R, Beach K, McManus CA, Xu SJ, Zhang S, Heller EA, Shen L, Nestler EJ, 2023. Cell Type-Specific Whole-Genome Landscape of DeltaFosB Binding in the Nucleus Accumbens After Chronic Cocaine Exposure. Biol Psychiatry. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R123] You JC, Muralidharan K, Park JW, Petrof I, Pyfer MS, Corbett BF, LaFrancois JJ, Zheng Y, Zhang X, Mohila CA, Yoshor D, Rissman RA, Nestler EJ, Scharfman HE, Chin J, 2017. Epigenetic suppression of hippocampal calbindin-D28k by DeltaFosB drives seizure-related cognitive deficits. Nat Med 23, 1377–1383. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R124] You JC, Stephens GS, Fu CH, Zhang X, Liu Y, Chin J, 2018. Genome-wide profiling reveals functional diversification of ΔFosB gene targets in the hippocampus of an Alzheimer’s disease mouse model. PLoS One 13, e0192508. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R125] Yutsudo N, Kamada T, Kajitani K, Nomaru H, Katogi A, Ohnishi YH, Ohnishi YN, Takase K, Sakumi K, Shigeto H, Nakabeppu Y, 2013. fosB-null mice display impaired adult hippocampal neurogenesis and spontaneous epilepsy with depressive behavior. Neuropsychopharmacology 38, 895–906. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R126] Zachariou V, Bolanos CA, Selley DE, Theobald D, Cassidy MP, Kelz MB, Shaw-Lutchman T, Berton O, Sim-Selley LJ, Dileone RJ, Kumar A, Nestler EJ, 2006. An essential role for DeltaFosB in the nucleus accumbens in morphine action. Nat Neurosci 9, 205–211. [DOI] [PubMed] [Google Scholar]

[R127] Zhao Y, Ho P, Yih Y, Chen C, Lee WL, Tan EK, 2011. LRRK2 variant associated with Alzheimer’s disease. Neurobiol Aging 32, 1990–1993. [DOI] [PubMed] [Google Scholar]

PERMALINK

Persistent ΔFosB expression limits recurrent seizure activity and provides neuroprotection in the dentate gyrus of APP mice

Gabriel S Stephens

Jin Park

Andrew Eagle

Jason You

Manuel Silva-Pérez

Chia-Hsuan Fu

Sumin Choi

Corey P St Romain

Chiho Sugimoto

Shelly A Buffington

Yi Zheng

Mauro Costa-Mattioli

Yin Liu

AJ Robison

Jeannie Chin

Abstract

INTRODUCTION

MATERIALS AND METHODS

Mice.

Adeno-associated virus (AAV)-mediated gene transfer.

Electroencephalogram (EEG) recording.

Object location memory testing.

Slice electrophysiology recording.

In vitro assays of neuroprotection in conditions of hyperexcitability.

Immunohistochemical experiments.

Gene Ontology network analysis.

Hippocampal RNA extraction and RT-qPCR.

RNA sequencing (RNA-seq).

Statistics.

RESULTS

Prolonged inhibition of ΔFosB activity in DGCs exacerbates recurrent seizure activity in APP mice

Figure 1. Prolonged inhibition of ΔFosB activity in DGCs exacerbates recurrent seizure activity in APP mice.

Figure 2. Unlike abbreviated ΔFosB blockade, prolonged ΔFosB blockade does not ameliorate spatial memory deficits in APP mice.

Overexpression of ΔFosB decreases excitability of DGCs in NTG mice

Figure 3. Excitability of DGCs is reduced by ΔFosB overexpression and increased by ΔFosB blockade.

Blockade of ΔFosB activity reveals hyperexcitability of DGCs in APP mice

ΔFosB is neuroprotective in conditions of excitotoxicity

Figure 4. ΔFosB is neuroprotective in conditions of excitotoxicity.

ΔFosB epigenetically regulates hippocampal gene expression via discrete modes of gene regulation

Figure 5. ΔFosB epigenetically regulates hippocampal gene expression via discrete modes of gene regulation.

Table 1.

Figure 6. Summary model.

DISCUSSION

Supplementary Material

Highlights.

Funding:

REFERENCES

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases