Environmental exposure to common pesticide induces synaptic deficit and social memory impairment driven by neurodevelopmental vulnerability of hippocampal parvalbumin interneurons

Jessica Di Re; Leandra Koff; Yosef Avchalumov; Aditya K Singh; Timothy J Baumgartner; Mate Marosi; Lisa M Matz; Lance M Hallberg; Bill T Ameredes; Erin H Seeley; Shelly A Buffington; Thomas A Green; Fernanda Laezza

doi:10.1016/j.jhazmat.2024.136893

. Author manuscript; available in PMC: 2025 Apr 4.

Published in final edited form as: J Hazard Mater. 2024 Dec 16;485:136893. doi: 10.1016/j.jhazmat.2024.136893

Environmental exposure to common pesticide induces synaptic deficit and social memory impairment driven by neurodevelopmental vulnerability of hippocampal parvalbumin interneurons

Jessica Di Re ^a,^b, Leandra Koff ^a, Yosef Avchalumov ^a,¹, Aditya K Singh ^a, Timothy J Baumgartner ^a, Mate Marosi ^a,², Lisa M Matz ^c, Lance M Hallberg ^a,^d, Bill T Ameredes ^a,^d, Erin H Seeley ^e, Shelly A Buffington ^c,^f, Thomas A Green ^a, Fernanda Laezza ^a,^c,^*

PMCID: PMC11970102 NIHMSID: NIHMS2063442 PMID: 39706027

Abstract

Environmental exposure to pesticides at levels deemed safe by regulatory agencies has been linked to increased risk for neurodevelopmental disorders. Yet, the mechanisms linking exposure to these disorders remain unclear. Here, we show that maternal exposure to the pesticide deltamethrin (DM) at the no observed adverse effect level (NOAEL) disrupts long-term potentiation (LTP) in the hippocampus of adult male offspring three months after exposure, a phenotype absent in female offspring. Clonazepam, a GABAa receptor agonist, rescued this deficit, indicating impaired hippocampal GABAergic signaling. Recordings from CA1 pyramidal neurons, complemented by MALDI mass spectrometry imaging, showed an imbalance in excitatory/inhibitory tone. Using a combination of parvalbumin (PV)-Cre transgenic mice and hippocampal injection of designer receptors exclusively activated by designer drugs (DREADDs), we show that developmental DM exposure reduces hippocampal PV interneuron intrinsic firing. DREADD activation rescued both PV interneuron firing and LTP deficits. Complementary behavioral experiments revealed a deficit in social memory, a behavior relevant to autism spectrum disorder (ASD) symptomatology, which was restored by DREADD activation. Overall, these results establish a novel mechanistic link between maternal exposure to DM at the NOAEL and known cellular, circuital, and behavioral vulnerabilities, indicating it is a potential driver in the exposome of ASD.

Keywords: Exposome, Neurodevelopmental Toxicology, Social Dysfunction, Chemogenetic Receptors, Autism Spectrum Disorder, E/I Tone

Graphical Abstract

graphic file with name nihms-2063442-f0007.jpg

1. Introduction

Significant attention has been directed towards understanding the impact of the environment in disease etiology [1,2]. This is particularly relevant in neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). These disorders are characterized by increased gene-environmental interactions [3,4] and are further complicated by a higher risk of toxicant exposure during early childhood, a period of critical vulnerability [5], and increased exposure due to proximity to areas of application [6].

One class of concerning environmental toxins are pyrethroid pesticides, which are broadly used in households, schools, and agriculture, and have been deemed safe despite evidence of increased juvenile toxicity, and neurotoxicity in humans and in preclinical models [7–9]. A hair sample analysis from pregnant mothers and 3.5-year-old children confirmed ubiquitous pyrethroid exposure during critical periods of development, as all samples tested positive for pyrethroid metabolites [10,11]. In humans, pyrethroid exposure has been linked to intellectual disability and exposure to a specific pyrethroid, deltamethrin (DM), was linked to increased diagnosis of ADHD [12–14]. Preclinical models of exposure at the no observed adverse effect level (NOAEL) dose established by the US Environmental Protection Agency have shown that DM alters brain circuitry and behaviors related to ADHD and ASD [14–18]. Overall, this indicates that pyrethroids in general, and DM specifically, may be environmental drivers in the exposome of neurodevelopmental disorders [19]. However, the mechanism by which these alterations in brain circuitry and behaviors arise following neurodevelopmental exposure to DM is not characterized, nor the extent to which these alterations mimic the proposed mechanisms of human disease. Identifying biological mechanisms triggered by early-life environmental exposure to DM will be essential for designing countermeasure strategies, mitigating risk, and developing individual resilience against neurodevelopmental disorders.

DM, used for its insecticidal properties, targets the insect voltage-gated Na+ (Nav) channels, but has demonstrated cross-reactivity with mammalian Nav (Nav1.1-Nav1.9) channels with potency and selectivity that vary across the nine isoforms (Nav1.1-Nav1.9) [20]. Crucially, neurotoxicology studies have underscored the specific susceptibility of mammalian Nav1.1 channels, critical for action potential firing in fast-spiking parvalbumin (PV) interneurons, to DM compared to other Nav channel isoforms [21]. Due to maturation and circuitry integration occurring during the postnatal critical period, PV interneurons are highly vulnerable in neurodevelopment [22]. In the hippocampus, a hub for information integration in the brain which may be disrupted in ASD [23,24], PV interneurons account for approximately a quarter of all GABAergic interneurons [25]. As the main source of GABAergic signaling, PV interneurons are necessary to maintain the excitatory-inhibitory (E/I) balance in the hippocampal circuitry. In turn, a balanced E/I tone is required for long-term potentiation (LTP) [25–27], a form of synaptic plasticity underlying episodic memory formation and social memory [28–30]. Dysfunction of hippocampal PV interneurons, imbalance in the E/I tone, and disrupted social memory have all been implicated in the etiology of ASD [30–36]. Altogether, this led to the hypothesis that environmental exposure to DM may trigger a sequalae of cellular, circuitry, and behavioral phenotypes driven by PV interneuron dysfunction as a primary contributor to ASD-like pathology.

In support of this hypothesis, we show that maternal exposure to the NOAEL of DM leads to significant deficits in hippocampal GABAergic signaling, disrupting LTP and social memory in adult male offspring. These phenotypes are rescued by selective chemogenetic activation of PV interneurons in the hippocampus through targeted injection of excitatory designer receptors exclusively activated by designer drugs (DREADDs), followed by tissue or systemic delivery of the highly potent DREADD ligand JHU37160. Overall, these results represent the first mechanistic study in environmental neurotoxicology on the effects of DM exposure, not only underscoring its role as a key driver in exposome of individuals with ASD, but also highlighting a potential pathway for therapeutic intervention to mitigate the effects of toxic exposure based on restoring PV interneuron function.

2. Materials and methods

2.1. Dosing

Virgin 8-week-old female C57BL/6 J mice (Jackson Lab, Bar Harbor, ME, USA) were paired with homozygous male B6.129P2-Pvalb^{tm1(cre) Arbr}/J (B6 PV^cre) or C57BL/6 J mice in breeding trios (two females per male) to produce offspring. A total of 25 C57BL/6 J (n = 12 control, n = 13 control) litters and 26 B6.129P2-Pvalb^tm1(cre)Arbr/J (B6 PV^cre) (n = 13 DM, n = 13 control) were produced. Dosing was performed as previously described, with slight modification [14,16]: beginning at pairing, females were given 3 mg/kg deltamethrin (Sigma-Aldrich, St. Louis, MO, USA) dissolved in corn oil and peanut butter in a 2:1 ratio, or corn oil and peanut butter alone (vehicle), stored in borosilicate glass at 4 °C. Dams were weighed immediately before preparing the appropriate dose, which was administered through syringe feeding to ensure accurate dosing. Dams were dosed every 72 h for a final dose of 1 mg/kg/day (total volume = 3 μL per gram body weight). A palatable vehicle was chosen to encourage voluntary consumption and avoid oral gavage which may cause unnecessary stress during pregnancy. 2 weeks after pairing females were separated from their cage mates and single housed until parturition of pups. Dosing continued until offspring were weaned at P21, at which point exposure to DM ceased. All animals were housed and maintained in a controlled environment (temperature 22 °C; relative humidity, 50 %; 12 h light/dark cycle) with free access to food and water. All surgical and experimental procedures employed were approved by the University of Texas Medical Branch Institutional Animal Care and Use Committee.

2.2. Evoked extracellular field potential recordings

C57BL/6 J (Fig. 1, Fig. 2) or heterozygous B6 PV^cre (Fig. 4) Mice were anesthetized using isoflurane (Baxter), quickly decapitated, and then brains were quickly dissected in ice-cold ACSF containing: 125 mM NaCl, 25 mM glucose, 25 mM NaHCO3, 2.5 mM KCl, 2 mM CaCl2, 1.25 mM NaH2PO4, and 1 mM MgCl2. 400 μm coronal slices containing the hippocampus were prepared using a vibratome (Leica Biosystems). 2–3 slices were immediately transferred to a submerged-type recording chamber (Kerr Scientific Instruments, Christchurch, NZ) and incubated at room temperature for at least 2 h, with remaining slices being stored in a submerged-type bath (Brain Slice Keeper, BSK4, Scientific Systems Design Inc, Mississauga, Ontario, CA) filled with ACSF until use. Slices were constantly perfused at a rate of 2 mL/min with oxygenated ACSF maintained at room temperature. Recordings were conducted in the CA1 region of the hippocampus after 2 h of incubation. Evoked field excitatory post synaptic potentials (fEPSP) were recorded from the CA1 striatum radiatum region of the hippocampus using a single Teflon coated 50 μm tungsten wire electrode and stimulation was delivered to the CA3 region using a bipolar Teflon coated 50 μm tungsten wire electrode connected to a stimulus isolator (ISO-Flex, A.M.P.I, Jerusalem, Israel) at the baseline rate of 0.033 Hz. Stimulation intensity was set at 30–40 % of saturating intensity. Input/output was used to determine maximum response and general slice health. For each slice, an input/output curve was constructed from 10 to 80 V, and paired-pulse responses were recorded at 50 m sec delay. LTP was induced by HFS at 100 Hz for 1 second. fEPSP slope was measured and the last 5 minutes of recordings were averaged to compare between groups. Slices were discarded if the baseline was not stable for at least 15–30 min. All the drugs that were used were given before the baseline stimulation. For DREADD experiments (Fig. 4), the water-soluble DREADD ligand JHU37160 (JH60, HelloBio, Princeton, NJ) was dissolved in milliQ water, then diluted in recording solution for a final concentration of 100 nM. DREADD experiments were performed in slices from animals that previously undergone behavioral testing, but received only saline.

Fig. 4. — Chemogenetic activation of PV interneurons rescues synaptic plasticity deficits induced by maternal DM exposure A. Schematic of effects of JHU31760 (JH60) on PV interneurons from B6 PV^cre mice expressing hM3D(Gq)-mCherry used in this figure. JH60 induces intracellular Ca2 + responses and depolarization increasing neuronal firing. B. Representative traces of whole-cell current clamp recordings of PV interneuron firing in hippocampal slices obtained from a DM-exposed B6 PV^cre male mouse before and C. after application of JH60 (100 nM). D. Input/output curve shows that JH60 restores the number of action potentials evoked in response to injected current steps of progressively increasing amplitude in the DM group and E. Application of JH60 increases the maximum number of action potentials fired by PV interneurons. F. Representative traces of hippocampal extracellular field recordings before and after LTP induction from control (vehicle-exposed, dark and light gray) or DM exposed male (orange and gold) B6 PV^cre offspring performed in the presence of either saline (gray, orange) or JH60 (light gray, gold) containing recording solution JH60 (100 nM). The recording schematic is as in Fig. 1A. G. % EPSP slope before and after tetanic (100 Hz, 1 s) stimulation at the CA3-CA1 Schaeffer’s collaterals in the experimental groups indicated in panel F. H. Activating PV interneurons decreases LTP in slices from control B6 PV^cre males (light gray) compared to slices recorded without JH60 (dark gray). Slices from DM-exposed B6 PV^cre males recorded without JH60 showed a deficit in LTP compared to slices from control animals treated with saline. Increasing PV interneuron firing with JH60 rescues LTP in DM-exposed males (yellow), increasing the fEPSP slope compared to both slices from DM-exposed animals recorded without JH60 and slices from control animals recorded with JH60. * * indicates p < 0.01 by two-way RM ANOVA (D), Wilcoxon matched-pairs signed rank test (E) or two-way mixed model ANOVA with Šídák’s multiple comparisons test. All data are mean ± SEM. Horizontal dashed lines indicate baseline (100 % fEPSP slope).

The following modifications were made to recording protocols for nucleus accumbens (NAc) and ventral pallidum (VP). For the VP, both stimulating and recording electrodes were placed in the VP core, approximately, 300–400 μm apart and LTP was induced with 100 Hz for 1 s, twice, 20 s apart. For NAc, the artificial cerebrospinal fluid (ACSF) contained 126 mM NaCI, 10 mM Glucose, 18 mM NaHCO3, 2.5 mM KCI, 2.4 mM CaCI2, 1.2 mM MgCl2, and 1.2 mM NaH2PO4 [37]. Both stimulating and recording electrodes were placed in the NAc core, approximately 400–500 μm apart. LTP in NAc was induced with 100 Hz for 1 s, twice, 20 s apart at 40 %-50 % maximal stimulation intensity [38].

2.3. Stereotaxic Surgery

Heterozygous B6 PVcre mice were anesthetized with isoflurane (Baxter, Deerfield, IL, USA) and injected bilaterally with AAV2-hSyn-DIO-hM3D(Gq)-mCherry in the hippocampus using stereotaxic coordinates (Dorsal hippocampus: AP = −1.9, L = 1.7, V = − 1.6; Ventral hippocampus: AP: −3.3, L:2.6, V:−4,−3,−2). As previously described, these coordinates do not result in total hippocampal coverage, but does result in coverage of a large area of the hippocampus [39]. 0.5 μl was injected into each posterior/ventral coordinate (total of 1.5 μl into ventral hippocampus) and 1.0 μl was injected into the dorsal/ventral coordinates. After each injection of 1.5 or 1.0 μl, the needles remained in place for 5 (ventral) or 10 (dorsal) additional minutes in order to allow for spread of the vector and to prevent the vector from spreading up the needle track. pAAV-hSyn-DIO-hM3D(Gq)-mCherry was a gift from Bryan Roth (Addgene viral prep # 44361-AAV2) [40].

2.4. Whole-cell patch clamp recordings in current clamp mode

Three weeks after heterozygous B6 PV^cre mice were stereotaxically injected, and following behavioral testing, 300 μM coronal or longitudinal brain slices containing the CA1 region were prepared as previously described. Only animals who received saline injections during behavior were used for testing. After slices were prepared, they were transferred from ice cold and continuously oxygenated (95 % O2/5 % CO2) tris-based cutting solution comprised of the following salts: 125 mM NaCl; 2.5 mM KCl; 20 mM HEPES; 1.25 mM Na2HPO4; 30 mM NaHCO3; 20 mM HEPES; 25 mM glucose; 3 mM Na pyruvate; 5 mM Na ascorbate; 5 mM MgCl2 and 0.5 mM CaCl2 (pH = 7.4 and osmolarity = 300–310 mOsm; all salts purchased from Sigma-Aldrich, St. Louis, MO, USA) to heated (37 °C) and continuously oxygenated tris-based cutting solution for 15 min. After 15 min, slices were transferred to heated (37 °C) and continuously oxygenated standard artificial cerebrospinal fluid (aCSF) comprised of the following salts: 125 mM NaCl; 2.5 mM KCl; 10 mM glucose; 1.2 mM MgCl2; 2.5 mM CaCl2; 25 mM NaHCO3; and 1.25 mM Na2HPO4 (pH = 7.4 and osmolarity = 300–310 mOsm; all salts were purchased from Sigma-Aldrich). After allowing ample recovery time, slices were transferred to the recording chamber, which was perfused with heated (37 °C) and continuously oxygenated aCSF at a flow rate of 150 mL/h.

Whole cell clamp-current recordings were then performed in mCherry positive PV interneurons in the CA1 hippocampal region. Current-clamp recordings with performed using pipettes filled with the following internal solution: 145 mM K-gluconate; 2 mM MgCl2; 0.1 mM EGTA; 2.5 mM Na2ATP; 0.25 mM Na2GTP; 5 mM phosphocreatine; and 10 mM HEPES (pH = 7.2 and osmolarity = 290 mOsm; all salts were purchased from Sigma-Aldrich). After GΩ seal formation and entry into the whole-cell configuration, membrane capacitance and series resistance were compensated for as described above. After compensation, the amplifier was switched to I = 0 mode for 1–2 mins to assess resting membrane potential. During this 1–2 min interval in I = 0 mode, a cocktail of synaptic blockers (20 μM bicuculline, 20 μM NBQX, and 100 μM AP-5; synaptic blockers purchased from Tocris (Bristol, UK)) was perfused to block changes in excitability driven by synaptic inputs. After determination of the resting membrane potential, the amplifier was switched to current-clamp mode, and the protocol shown in Fig. 3C was used to assess intrinsic excitability. To assess the input resistance, hyperpolarizing injected currents were applied (−120 mV to 0 mV; Δ 20 pA; 500 ms). As in the field recordings, for DREADD experiments JH60 was dissolved in milliQ water, then diluted in recording solution for a final concentration of 100 nM.

Fig. 3. — Maternal DM exposure impairs PV interneuron firing.A. Scheme of injection for pAAV-hSyn-DIO-h3MD(Gq)-mCherry into the hippocampus of B6.129P2-Pvalb^tm1(cre)Arbr/J male offspring of exposed dams. B. Triple labeling of PV interneurons in the hippocampus, as shown by colocalization of mCherry (red), parvalbumin (green) and the neuronal marker NeuN (blue). C. Anatomical map of the hippocampus with inset denoting mCherry (red) positive PV interneurons in the CA1 region. Scheme of whole-cell patch clamp recordings and stimulation protocol are shown at the bottom left. Representative examples of evoked action potentials from male offspring from dams exposed to D. vehicle or E. DM. F. DM exposure results in decreased action potentials at multiple current steps. G. DM exposure leads to reduced instantaneous firing frequency (IFF) at all injected currents between 50 and 220 pA. H. The maximum number of action potentials was decreased in DM-exposed males and I. maximum IFF were significantly decreased in DM-exposed males. J. The action potential voltage threshold was not impacted by exposure to DM, but K. current threshold was decreased following maternal exposure to DM. * indicates p < 0.05 and * * indicates p < 0.01 by two-way RM ANOVA with Šídák’s multiple comparisons test (F,G), two-tailed student’s t-test (H, K) or two-tailed student’s t-test with Welch’s corrections (I). All data are mean ± SEM.

2.5. Whole-cell patch clamp recordings in voltage clamp mode

Spontaneous IPSC and EPSC recordings were performed in visually identified CA1 pyramidal neurons. sIPSC recordings were performed using borosilicate glass pipettes containing the following internal solution: 130 mM Cesium methanesulfonate; 5 mM CsCl, 2 mM MgCl2 and 20 mM HEPES (pH = 7.2 and osmolarity = 285 mOsm; all salts were purchased from Sigma-Aldrich). sEPSC recordings were performed using borosilicate glass pipettes containing the following internal solution: 145 mM K-gluconate; 2 mM MgCl2; 0.1 mM EGTA; 2.5 mM Na2ATP; 0.25 mM Na2GTP; 5 mM phosphocreatine; and 10 mM HEPES (pH = 7.2 and osmolarity = 290 mOsm; all salts were purchased from Sigma-Aldrich). After GΩ seal formation and entry into the whole-cell configuration, membrane capacitance and series resistance were compensated for as described above. After compensation, the amplifier was switched to I = 0 mode for 1–2 mins to assess resting membrane potential of each cell. During this 1–2 min interval in I = 0 mode, a solution of 20 μM NBQX, and 100 μM AP-5; (Tocris, Bristol, UK) was perfused in order to isolate IPSCs or 20 μM bicuculline (Tocris) was perfused in order to isolate EPSCs. After assessment of resting membrane potential, cells were kept at a holding potential of −70 mV, and synaptic activity was recorded for 3 minutes. Frequency and amplitude of synaptic events were quantified using SynaptoSoft mini analysis software.

2.6. MALDI imaging

Three weeks after heterozygous B6 PV^cre mice were stereotaxically injected, and following behavioral testing, 12 μm sections were collected at 2 anatomical levels corresponding to the dorsal and ventral hippocampus for a total of 6 control and 6 DM-exposed slices. Only animals who received saline injections during behavior were used for testing. Serial sections were H&E stained and scanned using a Hamamatsu (San Jose, CA, USA) NanoZoomer SQ digital slide scanner. Sections were coated with 7 mg/mL N-(1-naphthyl) ethylenediamine dihydrochloride in 70 % methanol using an HTX (Chapel Hill, NC, USA) M5 Robotic Reagent Sprayer. Spray parameters were as follows: 8 passes, flow rate of 120 μL/min, track speed of 1200 mm/min, track spacing of 2 mm, nozzle temperature of 75 °C, and a nozzle height of 40 mm. Images were collected in negative ion mode at 50 μm resolution using a Bruker (Billerica, MA, USA) timsTOF fleX QTOF mass spectrometer. Data were collected over the m/z range 50–1000 with 300 laser shots summed per pixel. Acquisition parameters were optimized for metabolites as follows: a Funnel 1 RF of 175.0 Vpp, a Funnel 2 RF of 200.0 Vpp, a Multipole RF of 225.0 VPP, a Collision Energy of 10.0 eV, a Collision RF of 600.0 VPP, a Quadrupole Ion Energy of 5.0 eV, a Transfer Time of 60 μs, and a Pre Pulse Storage of 5 μs. Images were visualized using SCiLS Lab 2024b Pro (Bruker) and metabolites were identified using MetaboScape (Bruker).

2.7. Immunohistochemistry

Stereotaxically injected heterozygous B6 PV^cre mice were deeply anesthetized via isoflurane, followed by cardiac perfusion with PBS, then 4 % PFA. Brains were removed and post-fixed with 4 % PFA for 24 h, followed by overnight cryoprotection using 20 % sucrose, then embedded in OCT. 30 μm free floating sections were collected using a Leica cryostat and place in antigen preservation solution (Neuroscience Associates, Knoxville, TN, USA). Staining was performed as previously described [41]. Briefly, following washing with 1x PBS, slices were permeabilized in 1 % triton, 0.5 % tween for 7–10 min. Slices were then briefly washed with 1x PBS, followed by 1 hour blocking with normal goat serum (Catalog number: 50062Z, ThermoFisher, Waltham, MA, USA). The following antibodies were diluted in 3 % BSA in PBS and 0.1 % Tween-20 and incubated overnight at 4 C: guinea pig anti-NeuN (1:500, Synaptic System, catalog number 266004) and rabbit anti-Parvalbumin (1:1000, abcam ab11427). Following incubation, slices were again washed with PBS, followed by incubation with isotype specific secondary antibodies (Catalog # A-21450 and A-11034) at 1:250 for 1 h at room temperature. Following additional washing, slices were counterstained with DAPI, washed again with PBS and mounted to glass slides. Following a brief drying period to adhere to slides, slices were rinsed with water, dried in a 30 C drying oven, then coverslips were mounted using ProLong Gold.

2.8. Confocal imaging

Confocal images were acquired with a Zeiss LSM-880 with Airy scan confocal microscope. Multi-track acquisition was done with excitation lines at 405 for DAPI, 488 nm for Alexa 488, 561 nm for mCherry and 633 nm for Alexa 647. A 5× air (0.25 NA) objective was used for whole brain tile scans. Images of the CA1 were taken using a 20× air (0.8NA) objective and single-cell images were acquired using a 63× oil (1.4 NA) objective. Images were taken with a pixel dwell time of 0.42 μs (5×, 63×) or 0.77 μs (20x). Step sizes were as follows: 12.53 μm (5×), 0.98 μm (20×), and 0.45 μm (63×).

2.9. Open field testing (OFT)

Prior to behavioral testing, stereotaxically injected heterozygous B6 PV^cre mice were acclimated to handling for 5 consecutive days for 2–3 min per day. All behaviors were performed during the light cycle and animals were allowed to habituate to the testing room for 1 hour prior to testing. 10 minutes prior to testing, animals were injected with 0.1 mg/kg JH60 (dissolved in saline) or saline only. Dosing was randomly assigned to each animal at the outset of behavior, with treatment kept consistent throughout behavioral testing. This dose of JH60 has not been reported to have off target effects on behavior [42]. On days 1 and 2 of OFT, animals were given saline only to habituate to i. p. injection prior to injection with JH60. Open field testing was performed in an acrylic chamber without bedding, with the exterior covered in white contact paper. Total distance traveled over 40 minutes and distance traveled in the center zone were recorded and tracked using AnyMaze software (Stoelting Co, Wood Dale, IL, USA). The first 5 minutes of testing was excluded from analysis to avoid habituation effects [43]. Open field testing was performed over three consecutive days.

2.10. Novel object recognition (NOR)

NOR testing was performed in the same chambers as open field testing, allowing animals to habituate to the testing apparatus. On the first day of testing, 24 h after the final day of OFT, a randomly assigned training object (ice pack or stacked plates) were placed in opposite corners of the testing apparatus, approximately 7 cm away from the chamber wall. The training objects were randomly assigned to each animal and orientation of the objects was counterbalanced to prevent side-preference effects. Animals were allowed to explore for 10 min to learn the object. 24 h later, one of the objects was switched to determine preference for the novel object. Location of the novel object was counterbalanced, again to prevent side-preference effects. Each 10-min trial was recorded using AnyMaze software and time spent interacting with each object was scored by a blinded experimenter. Time spent sniffing, touching, or exploring the object was considered interacting, while time spent on top of the object was not.

2.11. Sociability and preference for social novelty testing

Crawley’s 3 C test for sociability and preference for social novelty was performed as previously described [44]. Briefly, 3–7 days after NOR testing, animals were habituated for 10 minutes in a 60 × 40 × 23 cm arena divided into three interconnected chambers. Sociability was measured during a second 10-minute interval in which the test subject could interact either with an empty wire cup (Empty) or a wire cup containing an age- and sex-matched stranger conspecific (Mouse 1). Stranger mice were acclimated to restraint in the wire cup during three training periods, over a period of two days prior to the test. Preference for social novelty was assayed in a third 10-minute interval by introducing a second stranger mouse (Mouse 2) into the previously empty wire cup. The location of the Empty Cup/Mouse 2 versus Mouse 1 were counterbalanced within cohorts and randomly assigned to testing animals. Interactions were again recorded by ANY-maze software and scored by a blinded experimenter, as several animals were observed self-grooming in proximity to the wire cups [45]. Similar to NOR testing, time spent sniffing, touching, or exploring the wire cup or stranger mouse was considered interacting, while time spent on top of the wire cup or self-grooming in proximity to the cup was not scored.

2.12. Statistical analysis

For all statistical tests, normal distribution was first checked to determine whether a parametric statistical test should be used to determine significance, or if a non-parametric equivalent (in the case of t-test) or log-normalization of the data (in the case of two-way ANOVA) should be used, except in the case of sIPSCs and sEPSCs, in which case a Kolmogorov-Smirnov test was used. In the case of electrophysiological measurements, the cell was considered the biological unit. To account for litter effects in behavioral testing, a three-way mixed model ANOVA was first used to exclude litter effects in behaviors. All statistical tests were performed in Prism 10 (GraphPad Software, Boston, MA) Specific statistical tests are outlined in figure legends. In all cases, p < 0.05 was considered statistically significant.

3. Results

3.1. Disrupted hippocampal GABAergic signaling induced by maternal DM exposure

The mode of action of DM is known to be via interactions with the Nav channel. However, DM’s potency varies among different isoforms, with DM being particularly active on mammalian Nav1.1 channels [21]. These channels are abundant in fast-spiking PV interneurons that are critical for hippocampal synaptic plasticity and memory formation [46], and their reduced activity has been linked to conditions such as ASD and Dravet syndrome [36,39,47]. Based on this premise, we sought to determine whether maternal exposure to DM could impact offspring neurodevelopment, with effects persisting into adulthood. We exposed dams during pregnancy and lactation to the NOAEL dose of DM (1 mg/kg/day) [14–18] and assessed potential DM neurotoxicity on offspring from weanling to adulthood (Fig. 1A).

Using extracellular field recordings, we found that three months after the cessation of exposure (P120), exposed males had intact basal synaptic transmission and short-term plasticity at the CA3 Schaeffer’s collaterals to CA1 inputs (Fig. 1B) as indicated by input-output relationship (p = 0.8326) and paired-pulse ratio (p = 0.6068, n = 11 control slices from 6 animals/ 6 litters, n = 12 DM from 7 animals/ 7 litters, control mean = 1.37 ± 0.09, DM mean = 1.356 ± 0.13). Likewise, females at P120, have intact basal synaptic transmission and short-term plasticity at the CA3 Schaeffer’s collaterals to CA1 inputs as indicated by input-output relationship (p = 0.5941) and paired-pulse ratio (p = 0.8479, n = 25 control from 14 pups/ 7 litters, n = 18 DM from 11 animals/8 litters control mean = 1.41 ± 0.08, DM mean = 1.39 ± 0.10), respectively (Fig. 1C). These results are in line with previous reports of paired-pulse plasticity studies at the CA3 to CA1 synapses, which show a paired-pulse ratio of approximately 1 [48]. However, exposed males showed remarkable deficits in CA1 long-term potentiation (LTP) in response to Schaeffer’s collaterals tetanic stimulation (100 Hz, 1 s Fig. 1D), indicating major deficits in long-term synaptic plasticity (p = 0.0056, n = 11 control from 6 animals/ litters, n = 12 DM from 7 animals/ litters, control mean = 170.07 ± 21.64, DM mean = 98.53 ± 10.217). In contrast, exposed females appeared protected from DM’s toxicity, showing intact LTP (p = 0.6698, n = 25 control from 14 pups/ 7 litters, n = 18 DM from 11 animals/8 litters, control mean = 177.88 ± 15.64, DM mean = 182.71 ± 17.51) (Fig. 1E) in line with previous reports that males are more sensitive to the effects of maternal DM exposure [14,15]. Furthermore, maternal DM exposure did not alter LTP within the ventral pallidum or nucleus accumbens (Supplemental Fig. 1), indicating that maternal DM exposure results in regionally specific deficits in LTP. Thus, we chose to focus on the effects of DM on exposed males, as females may be resistant to maternal exposure to DM.

To determine whether the mechanisms underlying these changes might be due to disrupted hippocampal GABAergic inhibitory tone, a common feature of ASD [49], we repeated our hippocampal extracellular field recordings in the presence of the GABAa receptor agonist clonazepam (CLZ) at a low concentration (500 nM). This concentration was previously shown to ameliorate changes in inhibitory signaling in a model of Dravet syndrome [50] and is supported by clinical use of benzodiazepines for treating ASD symptomatology [51]. In support of our hypothesis that GABAergic signaling causes LTP deficits in DM-exposed males, application of CLZ restored LTP to levels comparable to the vehicle-exposed control male mice (p = 0.2817, n = 11 control + DMSO (from 6 animals/3 litters), n = 12 DM + CLZ (from 6 animals/ 3 litters), control + DMSO mean = 264.55 ± 28.19, DM + CLZ mean = 179.91 ± 24.59) (Fig. 2A–C). As expected, the same CLZ treatment induced long-term depression (LTD) in slices from unexposed males compared to DMSO treated counterparts (p < 0.0001, n = 9 control + CLZ (from 6 animals/4 litters), control + CLZ mean = 33.35 ± 14.13) [52], as well as DM alone (p < 0.0001, DM data repeated from Fig. 1) and DM + CLZ (p < 0.0001). Treatment with CLZ likewise reduced basal synaptic transmission (Supplemental Fig. 2A), consistent with activation of concomitant feedforward inhibitory transmission mediated by CA1 recurrent collaterals. Application of CLZ did not alter short-term plasticity as indicated by the paired-pulse ratio (Supplemental Fig. 2B).

Next, we performed whole-cell patch-clamp recordings in CA1 pyramidal neurons (Fig. 2D) to determine whether the inhibitory tone in these cells was altered. We found that DM exposure significantly reduced the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in CA1 pyramidal neurons (p < 0.0001, n = 13 control neurons (from 3 animals/ 3 litters), n = 15 DM neurons (from 4 animals/4 litters)) (Fig. 2E,F), indicating reduced firing of inhibitory interneurons and a slight change in the amplitude of the sIPSCs (p < 0.0001) (Fig. 2G), which further corroborated a reduction in the inhibitory GABAergic tone in these cells. Concurrently, we also observed an increase in the frequency of spontaneous excitatory synaptic currents (sEPSCs) in CA1 pyramidal neurons (p < 0.0001, n = 6 control neurons from 3 animals/ 2 litters, n = 6 DM neurons from 3 animals/ 2 litters) (Fig. 2H,I) while their amplitude decreased (p = 0.0171) (Fig. 2J). This combined change in sIPSCs and sEPSCs, indicating an imbalance in the E/I tone, was supported by MALDI-MS imaging, which revealed an increased glutamate/GABA ratio in brain slices from DM-exposed mice compared to vehicle-exposed control mice (p = 0.0087, n = 6 control slices from 3 animals/ 2 litters) and n = 5 DM slices from 3 animals/ 3 litters); control mean = 3.41 ± 0.03, DM mean = 3.48 ± 0.10) (Fig. 2K–O).

Overall, these results indicate that maternal DM exposure leads to a loss of GABAergic signaling in male offspring, leading to disrupted hippocampal long-term plasticity, which can be restored by low-dose CLZ. Additionally, the decrease in sIPSC frequency in CA1 pyramidal neurons suggests reduced firing of GABAergic interneurons in the hippocampal circuitry, potentially driving the E/I tone imbalance.

3.2. DM-induced changes in GABAergic signaling are rescued by chemogenetic activation of PV interneuron firing

GABAergic signaling within the hippocampus is complex, involving feedforward and feedback inhibition mediated by specialized subtypes of GABA interneurons [53], which synapse onto pyramidal neurons, form reciprocal connections, and create auto-inhibitory connections [54]. One subtype which has repeatedly been implicated in ASD and accounts for the vast majority of the GABAergic tone on CA1 pyramidal neurons is PV interneurons. Having demonstrated a loss in GABAergic signaling induced by exposure to DM, we next tested whether the intrinsic electrophysiological properties of PV interneurons were affected by maternal DM exposure. To do so, we injected a CRE-dependent chemogenetic viral vector (pAAV-hSyn-DIO-hM3D (Gq)-mCherry) into the hippocampus of B6 PV^cre male mice (Fig. 3A, B). Two bilateral injections of this designer receptor exclusively activated by a designer drug (DREADD) [55] were performed (total of four injections) into the hippocampus of each mouse. As previously reported, these injections do not cover the entire hippocampus, but are sufficient to rescue hippocampal activity and behavior [39].

Whole-patch clamp recordings from mCherry labeled PV interneurons (Fig. 3C) showed that the expected effect of injected current (p < 0.0001, F (2.397, 45.55) = 238.7, n = 13 control and n = 8 DM cells, 3 animals per group, 2 litters and 3 litters respectively) and that maternal DM exposure decreased intrinsic action potential firing across a range of injected currents (p = 0.0007, F (1, 19) = 16.33,) and a Current x Exposure interaction (p < 0.0001, F (22, 418) = 6.769). (Fig. 3D–F). The same effects were also seen on instantaneous firing frequency (IFF, main effects of current: p < 0.0001, F (3.223, 61.24) = 435.6, n = 13 control and n = 8 DM cells, and DM exposure: p = 0.0003, F (1, 19) = 18.96. Current x Exposure interaction: p < 0.0001, F (22, 418) = 10.92) (Fig. 3G). Correspondingly, the maximum number of action potentials (Fig. 2H) and maximum IFF (Fig. 2I) were significantly decreased in DM-exposed males (Maximum action potentials: p = 0.0008 control = 21.00 ± 0.99; DM = 14.13 ± 1.49; Maximum IFF: p < 0.0001, control = 30.46 ± 1.32; DM = 21.86 ± 2.20). While the voltage-threshold of firing was unaffected by DM exposure (Fig. 3J), the current threshold of PV interneurons was significantly increased in hippocampal slices from DM-exposed males (p = 0.045, control =36.92 ± 4.14; DM = 50.00 ± 10.69)(Fig. 3K).

We then conducted another set of whole-cell patch clamp experiments in DREADD injected PV interneurons using the chemogenetic activator JHU37160 (JH60; Fig. 4A). Recordings were performed in either normal recording solution or in recording solution with JH60 (100 nM), as this a water soluble DREADD ligand. Application of JH60 to neurons injected with an excitatory DREADD, conferred by the Gq element of our vector, is intended to increase firing of neurons by increasing intracellular calcium [56]. Treatment with JH60 restored PV interneuron intrinsic firing across a range of injected currents (Effect of JH60: p = 0.0042, F (1, 7) = 17.32; Injected current x JH60 Interaction: p < 0.0001 F (22, 154) = 14.86) (Fig. 4B–E), and the maximum number of action potentials (p = 0.0234, DM mean = 8.38 ± 1.66, DM + JH60 mean = 22.38 ± 3.52), reaching levels comparable to offspring from control dams (Fig. 3D).

Next, hippocampal extracellular field recordings were conducted in slices from DREADD-injected animals, both in the absence and presence of JH60. An interaction between DREADD activation and DM exposure was seen (DREADD × exposure effect p < 0.0001, (F(1, 28) = 30.87). indicating a difference between control and DM-exposed animals in response to activating PV neurons. Consistent with the field recording experiments in wild-type mice (Fig. 1D), LTP was inhibited in B6 PV^cre males exposed to DM during development (p < 0.0001, n = 8 control B6 PV^cre + recording solution slices (8 animals/3 litters), n = 9 DM-exposed B6 PV^cre + recording solution slices (8 animals/ 3 litters)) (Fig. 4F–H). Crucially, chemogenetic activation of PV interneurons in DM-exposed animals restored LTP to control levels (DM-exposed B6 PV^cre + JH60; n = 7 slices, 6 animals/3 litters) (Fig. 4F–H), similar to the effect of low-dose CLZ (Fig. 2A–C). Likewise, in control (vehicle-exposed B6 PV^cre) mice, JH60 decreased the magnitude of LTP (p = 0.0027, n = 8 control B6 PV^cre + JH60, slices (8 animals/ 3 litters)) (Fig. 4F–H).

DM exposure did not alter basal synaptic transmission or short-term plasticity at the CA3-CA1 Schaeffer’s collaterals inputs, nor did DREADD activation with the ligand JH60 (Supplemental Fig. 3A,B). Overall, these results indicate that maternal DM exposure leads to a loss of PV interneuron firing, causing a reduction in hippocampal synaptic plasticity (LTP), which can be rescued by chemogenetic activation of these cells.

3.3. Maternal DM exposure impairs PV interneuron-dependent social memory

Extensive evidence shows that hippocampal PV interneurons play a key role in behaviors associated with ASD, particularly social memory [28,36]. Therefore, we sought to determine if disrupted PV interneuron function in the hippocampus induced by maternal DM exposure could lead to behavioral alterations associated with ASD in offspring and if chemogenetic activation of these interneurons could restore DM-driven phenotypes. Because the initial deficits in synaptic plasticity were sex-specific and only present in males, we elected to conduct our behavioral testing in male offspring. To determine the behavioral effects of maternal DM exposure in male offspring, we assessed differences in open field testing (OFT), novel object recognition (NOR), sociability, and social novelty [45,57] as these behaviors may be impacted by DM exposure or hippocampal PV interneuron activity [14,16,36,58]. Following maternal DM exposure, AAV-hSyn-DIO-hM3D(Gq)-mCherry was injected into the hippocampus of B6 PV^cre male mice (Fig. 5A). Vector injection sites were validated in all animals, with expression throughout the hippocampus and the most expression in dorsal and ventral CA1 (Fig. 5B).

Fig. 5. — Maternal DM exposure and PV neuron activity do not affect locomotor activity or long-term object recognition A. Timeline of exposure, AAV viral particle injection, and behavioral testing in control and DM-exposed B6 PV^cre males expressing the AAV-DIO-hM3D(Gq)-mCherry activating DREAAD construct in the hippocampus. Control refers to vehicle-exposed (dark and light gray) B6 PV^cre offspring; the DM-exposed group corresponds to male B6 PV^cre offspring (orange and gold). Behavioral testing was performed in the presence of either saline (gray, orange) or JH60 (light gray, gold) in each of the two groups. B. Representative injection showing neuronal marker (NeuN) and distribution of mCherry (red) in CA1 region i. throughout the hippocampus, **ii.** at AP −2.5, and **iii.** distribution within CA1. C. No difference was seen between groups: control + DREADD + saline (open circle/ dark gray), control + DREADD + JH60 (light gray), DM + DREADD + saline (Orange) or DM + DREADD + JH60 (yellow) in open field testing of overall locomotor behavior or D. Percent distance traveled in the center zone. E. All groups preferred the novel object over the familiar but no differences were seen between groups for time spent interacting with the familiar object or the novel object. No differences were seen between discrimination indices. * * indicates p < 0.01 by two-way RM ANOVA with Tukey’s multiple comparison’s test and all data are mean ± SEM.

Behavior testing began 3 weeks after injection, to allow for peak viral expression, which corresponded to P45–60 or 24–39 days after cessation of exposure. Since NOR requires repeated exposure to the testing arena to habituate the animals before testing, we performed our tests in the following order: OFT, NOR, 3-chamber test of sociability and social novelty. This also allowed time for the animals to habituate to handling and intraperitoneal (i.p.) injections during the first two days of OFT.

There have been mixed reports on the effects of maternal DM exposure and PV interneuron activity has been reported as not affecting locomotor activity [14,16,28]. Here, DM-exposure did not affect locomotor activity in the novel open field or on day 2 of OFT, during which all animals were injected with saline (i.p.) (Supplemental Fig. 4). On day 3 of OFT, mice were injected with either saline or 0.1 mg/kg JH60 (i.p.) 10 minutes before testing. First, A three-way mixed model ANOVA showed no effect of litter on OFT (p = 0.3059, F (5, 43) = 1.243) or time spent in the center zone (p = 0.7046 (F (5, 43) = 0.5940). No effect of DM or increased PV interneuron activity was seen on total distance traveled (DM exposure effect, p = 0.3446, F (1, 68) = 0.9059, JH60 effect, p = 0.2482, F (1, 68) = 1.357, n = 20 control + saline (8 litters), n = 20 control + JH60 (9 litters), n = 16 DM + saline (10 litters), n = 15 DM + JH60 (9 litters)) (Fig. 5C), or time spent in the center zone of an open field (DM exposure effect, p = 0.6869, F (1, 68) = 0.1638, JH60 effect, p = 0.6725, F (1, 68) = 0.1802) (Fig. 5D), indicating that neither DM exposure nor PV interneuron activity induced changes in locomotor behavior in mice.

Next, to determine whether maternal DM exposure disrupted long-term object recognition memory, we performed NOR testing at 24 h [59]. While previous reports of adult DM exposure indicate a change in exploratory behavior in NOR, we found that neither DM exposure nor PV-interneuron activity had an effect on NOR at 24 h, though this effect has previously not been tested in a model of maternal exposure [60]. Likewise, optogenetic inhibition of PV interneurons does not affect object recognition memory, though severe disruptions using tetanus toxin does [28]. Here, all groups preferred interacting with the novel object compared to familiar object (main effect of object: p < 0.0001, F (1, 67) = 86.97) and Tukeys’s multiple comparison’s testing showed that all groups preferred the novel object over the familiar (P < 0.001 for all conditions, control + saline familiar mean = 27.25 ± 2.37, control + saline novel mean = 50.29 ± 4.24, control + JH60 familiar mean = 24.97 ± 2.43, control + JH60 novel mean = 44.48 ± 5.25, DM + saline familiar mean = 28.88 ± 2.90, DM + saline novel mean = 53.5 ± 5.43, DM + JH60 familiar mean = 28.35 ± 2.98, DM + JH60 novel mean = 53.12 ± 5.30) (Fig. 5E). A three-way mixed model ANOVA showed no effect of litter on discrimination index (p = 0.8228, F (5, 43) = 0.43) and no differences were seen in discrimination index between groups (DM exposure effect: p = 0.8308, F (1, 67) = 0.04603; Effect of JH60: p = 0.7581, F (1, 67) = 0.09566). Overall, this indicates that male offspring from DM-exposed dams had intact object recognition memory and PV neuron activity did not affect object recognition memory.

Following open field and NOR testing, animals underwent a 3-chamber test of sociability and social novelty (Fig. 6A), which is a translationally relevant behavioral test measuring social preference and social novelty detection, or social memory [44,61]. Control animals injected with DREADDs receiving saline injections were able to discriminate between a novel social animal (M1) compared to a novel object (cup) and preferred to interact with the animal (p = 0.0010, control + saline cup mean = 88.21 ± 6.09, control + saline M1 mean = 123.34 ± 5.87), showing intact sociability (Fig. 6B). DM exposed males also showed a preference for the novel social animal over the empty cup (p < 0.0001 DM + saline cup mean = 83.71 ± 5.93, DM + saline M1 mean = 134.89 ± 9.15), as did JH60 injected control (p = 0.0014, control + JH60 cup mean = 79.15 ± 4.87, control + JH60 M1 mean = 113.15 ± 7.26) and DM-exposed (p = 0.0394,DM + JH60 cup mean = 81.53 ± 10.30, DM + JH60 M1 mean = 106.3 ± 9.60) males. A two-Way ANOVA showed no effect of DM exposure or JH60 on sociability index (DM exposure: p = 0.1600, F (1, 67) = 0.1089; JH60 effect: p = 0.7424; F (1, 67) = 0.3937). Overall, neither DM exposure nor PV neuron activation affected the sociability phase of testing.

In the social novelty phase of testing, in which a new social animal (M2) is placed inside the empty cup, preference for social novelty was intact in control animals injected with DREADDs and receiving saline injections prior to testing, as indicated by a preference for interacting with the novel social animal (M2) compared to the familiar animal from the previous phase (M1) (p = 0.0002 control + saline M1 mean = 63.22 ± 5.02, control + saline M2 mean = 96.57 ± 6.61) Fig. 6C). PV interneuron activation in control males impaired social novelty, such that these animals did not spend significantly more time with M2 compared to M1 (p = 0.1129, control + JH60 M1 mean = 65.93 ± 6.12, control + JH60, M2 mean = 79.40 ± 6.82). Similarly, DM-exposure diminished interaction with M2 compared to M1 (p = 0.3851 DM + saline cup M1 = 78.55 ± 5.99, DM + saline M2 mean = 86.74 ± 7.99), indicating that maternal exposure to DM impairs social memory in adult males. Crucially, PV interneuron activation in DM-exposed males rescued the impaired social memory (p < 0.0001, DM + JH60 M1 mean = 53.01 ± 5.51, DM + JH60 M2 mean = 96.33 ± 9.53). This resulted in a significant interaction effect of exposure to DM and DREADD activation on social novelty indices (p = 0.00074, F (1, 67) = 12.51), though a three-way ANOVA showed no effect of litter (F (5, 43) = 0.7513, p = 0.5897). While confirming that PV interneuron function is crucial for the formation of social memories [28,30,36,58], these results demonstrate that the toxic effects of maternal DM exposure leads to a loss in social memory arising from decreased PV interneuron activity in the hippocampus. As these deficits were not seen in object recognition memory, the memory deficits caused by maternal DM exposure appear specific to social memory, a core feature of ASD. Importantly, chemogenetic activation of PV interneurons in the hippocampus restores the social memory deficits induced by DM exposure.

4. Discussion

Extensive evidence links DM’s neurodevelopmental toxicity to persistent disruptions in brain health into adulthood. However, fully understanding how these disruptions relate to specific disease phenotypes, uncovering the underlying mechanisms, and developing effective rescue strategies remains a challenge. Our study demonstrates that maternal DM exposure during pregnancy and through weaning alters hippocampal GABAergic signaling, particularly PV interneuron function, leading to disrupted social memory in male offspring observed two and a half months post-exposure. Restoring PV interneuron function with an excitatory chemogenetic vector reverses both circuit-level abnormalities and behavioral deficits. These findings directly link a toxic mechanism to social memory deficits in ASD, providing insights into DM’s potential harm at levels considered safe in human exposure studies.

First, we found that DM exposure affects hippocampal plasticity exclusively in males, with the hippocampus being more susceptible than the striatum (Fig. 1). Overall, these results align with prior animal exposure studies [14,15,62], suggesting the hippocampus as a highly vulnerable brain region during development, and in line with the higher ASD diagnosis rate in males [63,64]. Future research should explore the nature of this sex specificity, particularly whether it stems from increased susceptibility of males due to known differences in toxicokinetics, particularly metabolism and excretion [65], or if females are more protected or develop resilience mechanisms following toxin exposure.

We focused on males to study impaired hippocampal plasticity, particularly CA3-CA1 LTP, crucial for learning and memory [46]. Low-concentration CLZ, a GABAα receptor agonist, restored LTP in DM-exposed males (Fig. 2). Clinical and experimental evidence supports CLZ’s efficacy in ASD, including restoring altered GABAergic signaling in models like Nav1.1 haploinsufficient and BTBR mice, which are genetic models of Dravet’s syndrome and idiopathic ASD, respectively [50, 51,66]. Additionally, in complementary patch-clamp electrophysiology in CA1 pyramidal neurons we showed that maternal DM exposure reduced sIPSC frequency while increasing sEPSC frequency (Fig. 2), indicating altered E/I balance in the hippocampus, consistent with previous findings on adult DM exposure in the hippocampus [67]. These results are further supported by our MALDI imaging, which showed an overall E/I imbalance (Fig. 2). Overall, these findings align with clinical use of low-dose CLZ, suggesting reduced GABAergic signaling as a hallmark of ASD [68], and reduced GABAergic signaling as a key factor of DM’s neurodevelopmental toxicity.

PV interneurons are the largest source of GABAergic tone and are enriched with Nav1.1 channels, which are uniquely sensitive to DM. PV interneurons mediate gamma frequency oscillations, which underlie memory formation and elicit LTP [69,70]; further, they are highly implicated in neurodevelopmental disorders, including ASD [30,32–35, 58]. In our study, we demonstrate that DM exposure leads to a reduction in PV interneuron intrinsic firing (Fig. 3), which is the mechanistic drive of inhibited LTP in DM-exposed mice, as the chemogenetic activator JH60 rescues this deficit (Fig. 4). These findings are pivotal, as they suggest that dysfunction in PV interneurons may represent a common, transdiagnostic hallmark across various neurodevelopmental disorders, irrespective of their genetic or environmental origins.

Though there is little direct evidence on the effect of reduced PV interneuron function on LTP, it is counterintuitive that a GABA receptor agonist or chemogenetic activation of PV interneurons restores LTP. Suppressing, rather than enhancing, the hippocampal GABAergic tone typically increases the chances of LTP. LTP induction in CA1 pyramidal neurons relies on NMDA receptor activation and requires postsynaptic depolarization [54]. GABAergic release from interneurons can attenuate CA1 pyramidal neuron depolarization (and NMDA receptor activation) or amplify it by causing disinhibition through reciprocal or auto-inhibitory connections [54]. In addition to synapsing onto CA1 pyramidal neurons, PV interneurons have both reciprocal connections via CCK interneurons and auto-inhibitory connections [22]. Thus, a possible explanation for the rescuing effect of JH60 and CLZ may be that they restore disinhibition, thereby correcting an imbalance that unevenly affects PV interneuron connectivity.

In contrast to existing literature on the impact of GABAergic signaling on LTP, to date there has only been one other report on the effects of developmental DM exposure on hippocampal LTP [15], which showed that direct DM exposure starting at P3 enhances hippocampal LTP in male rats [15]. This difference in exposure time may differentially affect PV interneuron development: though PV interneuron development peaks around P15, their precursors form during embryonic stages [71]. Thus, disrupting PV interneuron precursors in utero, combined with potential direct effects on PV interneurons during postnatal exposure, may lead to distinct phenotypes compared to postnatal exposure alone.

We conducted behavioral studies focusing on impaired social interactions in ASD, using Crawley’s 3-chamber test [72]. Male mice exposed to DM during development showed deficits specifically in social memory (Fig. 6), aligning with studies emphasizing the role of E/I tone and PV interneuron activity in the hippocampus for social memory [28–30,36,58,73]. Phillips et al. previously showed that both chronic stimulation and inhibition pyramidal neurons projecting from the ventral hippocampal to the medial prefrontal cortex result in deficits in social memory. Correspondingly, restoring E/I tone balance by increasing inhibition in a mouse model of genetic ASD rescues social memory deficits, overall suggesting that the proper balance of E/I tone in the hippocampus is necessary for intact social memory [58]. The specific effect of DM on social memory and not NOR is also in line with the effects of optogenetic inhibition of PV interneurons [28]. We saw no change in OFT due to either PV interneuron firing or DM exposure (Fig. 5). Reports of the effects of DM on locomotor activity are vary depending on time of exposure, species, testing environment or handling which is a likely explanation of our results [14–16,74,75].

5. Conclusion

Overall, we show here that maternal exposure to DM at NOAEL dosing impairs the activity of PV interneurons during adulthood, leading to disrupted plasticity and driving social memory deficits, a key feature of ASD. Thus, developmental DM exposure may be an environmental factor that drives risk of ASD development and a key element of the exposome of individuals with ASD. These findings address a critical need and align with the future of environmental health sciences in providing evidence of key mechanisms of toxicity that could inform countermeasures of exposure.

Environmental implications

Evidence suggests that humans are ubiquitously exposed to pyrethroid pesticides despite growing evidence that developmental exposure may increase risk of neurodevelopmental disorders. However, the mechanism linking this exposure to the risk is not well understood. Here, we show that maternal exposure to deltamethrin at the no observed adverse effect level impairs inhibitory brain signaling in exposed pups, leading to impaired long-term synaptic plasticity and impaired social memory, a key feature of autism spectrum disorder. Further, by selectively increasing inhibitory signaling in a key brain region linked to social memory, these deficits were rescued in pups exposed to deltamethrin during development.

Supplementary Material

NIHMS2063442-supplement-Supplementary_Material.pdf^{(702.6KB, pdf)}

HIGHLIGHTS.

Maternal exposure to deltamethrin led to loss of hippocampal LTP in male offspring.
Loss of LTP stemmed from E/I tone imbalance driven by loss of PV neuron function.
Male offspring had impaired social memory, a key feature of autism spectrum disorder.
Restoring PV neuron function rescued both LTP and social memory.

Funding

This research was supported by supported by T32ES007254 (JD), R01 HD109095–01A1 (SAB), R01 HD109780–01A1 (SAB), The Robert & Janice McNair Foundation, McNair Medical Institute (SAB), R21 ES034956 (FL), R01 ES031823 (FL, TAG), & P30ES030285 (FL). Mass Spectrometry Imaging was performed in the University of Texas at Austin Mass Spectrometry Imaging Facility supported by Cancer Prevention and Research Institute of Texas (CPRIT) award RP190617 (EHS).

Footnotes

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A. Supporting information

Supplementary data associated with this article can be found in the online version at doi:10.1016/j.jhazmat.2024.136893.

CRediT authorship contribution statement

Leandra Koff: Writing – review & editing, Writing – original draft, Visualization, Investigation, Formal analysis. Fernanda Laezza: Writing – review & editing, Writing – original draft, Supervision, Resources, Methodology, Conceptualization. Jessica Di Re: Writing – review & editing, Writing – original draft, Visualization, Project administration, Investigation, Formal analysis. Thomas A. Green: Writing – review & editing, Resources, Methodology, Funding acquisition. Shelly A. Buffington: Writing – review & editing, Resources, Methodology. Erin H. Seeley: Writing – review & editing, Resources, Investigation, Formal analysis. Bill T. Ameredes: Writing – review & editing, Resources, Methodology, Funding acquisition. Lance M. Hallberg: Writing – review & editing, Resources, Methodology. Lisa M. Matz: Writing – review & editing, Methodology. Mate Marosi: Writing – review & editing, Investigation, Formal analysis. Timothy J. Baumgartner: Writing – review & editing, Investigation, Formal analysis, Conceptualization. Aditya K. Singh: Writing – review & editing, Investigation, Formal analysis. Yosef Avchalumov: Writing – review & editing, Investigation, Formal analysis.

Data availability

Data will be made available on request.

References

[1].GBD 2021 Nervous System Disorders Collaborators, 2024. Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the global burden of disease study 2021. Lancet Neurol 23, 344–381. 10.1016/S1474-4422(24)00038-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
[2].Krause S, Ouellet V, Allen D, Allen S, Moss K, Nel HA, et al. , 2024. The potential of micro- and nanoplastics to exacerbate the health impacts and global burden of non-communicable diseases. Cell Rep Med 5, 101581. 10.1016/j.xcrm.2024.101581. [DOI] [PMC free article] [PubMed] [Google Scholar]
[3].Lipkin WI, Bresnahan M, Susser E, 2023. Cohort-guided insights into gene-environment interactions in autism spectrum disorders. Nat Rev Neurol 19, 118–125. 10.1038/s41582-022-00764-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
[4].Schwabe I, Jović M, Rimfeld K, Allegrini AG, van den Berg SM, 2024. Genotype-environment interaction in ADHD: genetic predisposition determines the extent to which environmental influences explain variability in the symptom dimensions hyperactivity and inattention. Behav Genet 54, 169–180. 10.1007/s10519-023-10168-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
[5].Sly PD, Flack F, 2008. Susceptibility of children to environmental pollutants. Ann N Y Acad Sci 1140, 163–183. 10.1196/annals.1454.017. [DOI] [PubMed] [Google Scholar]
[6].Hauptman M, Woolf AD, 2017. Childhood ingestions of environmental toxins: what are the risks? e466–e471 Pediatr Ann 46. 10.3928/19382359-20171116-01. [DOI] [PMC free article] [PubMed] [Google Scholar]
[7].Amaraneni M, Pang J, Mortuza TB, Muralidhara S, Cummings BS, White CA, et al. , 2017. Brain uptake of deltamethrin in rats as a function of plasma protein binding and blood-brain barrier maturation. Neurotoxicology 62, 24–29. 10.1016/j.neuro.2017.04.009. [DOI] [PubMed] [Google Scholar]
[8].Meacham CA, Brodfuehrer PD, Watkins JA, Shafer TJ, 2008. Developmentally-regulated sodium channel subunits are differentially sensitive to alpha-cyano containing pyrethroids. Toxicol Appl Pharmacol 231, 273–281. 10.1016/j.taap.2008.04.017. [DOI] [PubMed] [Google Scholar]
[9].Kim K-B, Anand SS, Kim HJ, White CA, Fisher JW, Tornero-Velez R, et al. , 2010. Age, dose, and time-dependency of plasma and tissue distribution of deltamethrin in immature rats. Toxicol Sci 115, 354–368. 10.1093/toxsci/kfq074. [DOI] [PubMed] [Google Scholar]
[10].Macheka LR, Palazzi P, Iglesias-González A, Zaros C, Appenzeller BMR, Zeman FA, 2024. Exposure to pesticides, persistent and non - persistent pollutants in French 3.5-year-old children: findings from comprehensive hair analysis in the ELFE national birth cohort. Environ Int 190, 108881. 10.1016/j.envint.2024.108881. [DOI] [PubMed] [Google Scholar]
[11].Béranger R, Hardy EM, Binter A-C, Charles M-A, Zaros C, Appenzeller BMR, et al. , 2020. Multiple pesticides in mothers’ hair samples and children’s measurements at birth: results from the French national birth cohort (ELFE). Int J Hyg Environ Health 223, 22–33. 10.1016/j.ijheh.2019.10.010. [DOI] [PubMed] [Google Scholar]
[12].Viel J-F, Rouget F, Warembourg C, Monfort C, Limon G, Cordier S, et al. , 2017. Behavioural disorders in 6-year-old children and pyrethroid insecticide exposure: the PELAGIE mother-child cohort. Occup Environ Med 74, 275–281. 10.1136/oemed-2016-104035. [DOI] [PubMed] [Google Scholar]
[13].Viel J-F, Warembourg C, Le Maner-Idrissi G, Lacroix A, Limon G, Rouget F, et al. , 2015. Pyrethroid insecticide exposure and cognitive developmental disabilities in children: the PELAGIE mother-child cohort. Environ Int 82, 69–75. 10.1016/j.envint.2015.05.009. [DOI] [PubMed] [Google Scholar]
[14].Richardson JR, Taylor MM, Shalat SL, Guillot TS, Caudle WM, Hossain MM, et al. , 2015. Developmental pesticide exposure reproduces features of attention deficit hyperactivity disorder. FASEB J 29, 1960–1972. 10.1096/fj.14-260901. [DOI] [PMC free article] [PubMed] [Google Scholar]
[15].Pitzer EM, Sugimoto C, Regan SL, Gudelsky GA, Williams MT, Vorhees CV, 2022. Developmental deltamethrin: sex-specific hippocampal effects in Sprague Dawley rats. Curr Res Toxicol 3, 100093. 10.1016/j.crtox.2022.100093. [DOI] [PMC free article] [PubMed] [Google Scholar]
[16].Jiménez JA, Simon JM, Hu W, Moy SS, Harper KM, Liu CW, et al. , 2022. Developmental pyrethroid exposure and age influence phenotypes in a Chd8 haploinsufficient autism mouse model. Sci Rep 12, 1–15. 10.1038/s41598-022-09533-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
[17].Curtis MA, Dhamsania RK, Branco RC, Guo J-D, Creeden J, Neifer KL, et al. , 2023. Developmental pyrethroid exposure causes a neurodevelopmental disorder phenotype in mice. PNAS Nexus 2, pgad085. 10.1093/pnasnexus/pgad085. [DOI] [PMC free article] [PubMed] [Google Scholar]
[18].Deltamethrin USEPA, 2004. Pesticide tolerance. Fed Regist 69, 62602–62615. [Google Scholar]
[19].Vermeulen R, Schymanski EL, Barabási A-L, Miller GW, 2020. The exposome and health: where chemistry meets biology. Science 367, 392–396. 10.1126/science.aay3164. [DOI] [PMC free article] [PubMed] [Google Scholar]
[20].Field LM, Davies TGE, O’Reilly AO, Williamson MS, Wallace BA, 2017. Voltage-gated sodium channels as targets for pyrethroid insecticides. Eur Biophys J 46, 675–679. 10.1007/s00249-016-1195-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
[21].James TF, Nenov MN, Tapia CM, Lecchi M, Koshy S, Green TA, et al. , 2017. Consequences of acute Nav1.1 exposure to deltamethrin. Neurotoxicology 60, 150–160. 10.1016/j.neuro.2016.12.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
[22].Abráhám H, Kojima H, Götzer K, Molnár A, Tornóczky T, Seress L, 2023. Development of parvalbumin-immunoreactive neurons in the postnatal human hippocampal formation. Front Neuroanat 17, 1058370. 10.3389/fnana.2023.1058370. [DOI] [PMC free article] [PubMed] [Google Scholar]
[23].Rexrode LE, Hartley J, Showmaker KC, Challagundla L, Vandewege MW, Martin BE, et al. , 2024. Molecular profiling of the hippocampus of children with autism spectrum disorder. Mol Psychiatry 1–12. 10.1038/s41380-024-02441-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
[24].Neufeld J, Maier S, Revers M, Reisert M, Kuja-Halkola R, Tebartz van Elst L, et al. , 2023. Reduced brain connectivity along the autism spectrum controlled for familial confounding by co-twin design. Sci Rep 13, 13124. 10.1038/s41598-023-39876-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
[25].Bezaire MJ, Soltesz I, 2013. Quantitative assessment of CA1 local circuits: knowledge base for interneuron-pyramidal cell connectivity. Hippocampus 23, 751–785. 10.1002/hipo.22141. [DOI] [PMC free article] [PubMed] [Google Scholar]
[26].Khlaifia A, Honoré E, Artinian J, Laplante I, Lacaille JC, 2022. mTORC1 function in hippocampal parvalbumin interneurons: regulation of firing and long-term potentiation of intrinsic excitability but not long-term contextual fear memory and context discrimination. Mol Brain 15, 1–16. 10.1186/s13041-022-00941-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
[27].Campanac E, Gasselin C, Baude A, Rama S, Ankri N, Debanne D, 2013. Enhanced intrinsic excitability in basket cells maintains excitatory-inhibitory balance in hippocampal circuits. Neuron 77, 712–722. 10.1016/j.neuron.2012.12.020. [DOI] [PubMed] [Google Scholar]
[28].Deng X, Gu L, Sui N, Guo J, Liang J, 2019. Parvalbumin interneuron in the ventral hippocampus functions as a discriminator in social memory. Proc Natl Acad Sci USA 116, 16583–16592. 10.1073/pnas.1819133116. [DOI] [PMC free article] [PubMed] [Google Scholar]
[29].Okuyama T, Kitamura T, Roy DS, Itohara S, Tonegawa S, 2016. Ventral CA1 neurons store social memory. Science 353, 1536–1541. 10.1126/science.aaf7003. [DOI] [PMC free article] [PubMed] [Google Scholar]
[30].Tao K, Chung M, Watarai A, Huang Z, Wang MY, Okuyama T, 2022. Disrupted social memory ensembles in the ventral hippocampus underlie social amnesia in autism-associated Shank3 mutant mice. Mol Psychiatry 27, 2095–2105. 10.1038/s41380-021-01430-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
[31].Paterno R, Marafiga JR, Ramsay H, Li T, Salvati KA, Baraban SC, 2021. Hippocampal gamma and sharp-wave ripple oscillations are altered in a Cntnap2 mouse model of autism spectrum disorder. Cell Rep 37, 109970. 10.1016/j.celrep.2021.109970. [DOI] [PMC free article] [PubMed] [Google Scholar]
[32].Selby L, Zhang C, Sun Q-Q, 2007. Major defects in neocortical GABAergic inhibitory circuits in mice lacking the fragile X mental retardation protein. Neurosci Lett 412, 227–232. 10.1016/j.neulet.2006.11.062. [DOI] [PMC free article] [PubMed] [Google Scholar]
[33].Gogolla N, Leblanc JJ, Quast KB, Südhof TC, Fagiolini M, Hensch TK, 2009. Common circuit defect of excitatory-inhibitory balance in mouse models of autism. J Neurodev Disord 1, 172–181. 10.1007/s11689-009-9023-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
[34].Filice F, Janickova L, Henzi T, Bilella A, Schwaller B, 2020. The parvalbumin hypothesis of autism spectrum disorder. Front Cell Neurosci 14, 577525. 10.3389/fncel.2020.577525. [DOI] [PMC free article] [PubMed] [Google Scholar]
[35].Juarez P, Martínez Cerdeño V, 2022. Parvalbumin and parvalbumin chandelier interneurons in autism and other psychiatric disorders. Front Psychiatry 13, 913550. 10.3389/fpsyt.2022.913550. [DOI] [PMC free article] [PubMed] [Google Scholar]
[36].Tatsukawa T, Ogiwara I, Mazaki E, Shimohata A, Yamakawa K, 2018. Impairments in social novelty recognition and spatial memory in mice with conditional deletion of Scn1a in parvalbumin-expressing cells. Neurobiol Dis 112, 24–34. 10.1016/j.nbd.2018.01.009. [DOI] [PubMed] [Google Scholar]
[37].Robbe D, Kopf M, Remaury A, Bockaert J, Manzoni OJ, 2002. Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens. Proc Natl Acad Sci USA 99, 8384–8388. 10.1073/pnas.122149199. [DOI] [PMC free article] [PubMed] [Google Scholar]
[38].Schramm NL, Egli RE, Winder DG, 2002. LTP in the mouse nucleus accumbens is developmentally regulated. Synapse 45, 213–219. 10.1002/syn.10104. [DOI] [PubMed] [Google Scholar]
[39].Stein RE, Kaplan JS, Li J, Catterall WA, 2019. Hippocampal deletion of NaV1.1 channels in mice causes thermal seizures and cognitive deficit characteristic of Dravet syndrome. Proc Natl Acad Sci USA 116, 16571–16576. 10.1073/pnas.1906833116. [DOI] [PMC free article] [PubMed] [Google Scholar]
[40].Krashes MJ, Koda S, Ye C, Rogan SC, Adams AC, Cusher DS, et al. , 2011. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J Clin Investig 121, 1424–1428. 10.1172/JCI46229. [DOI] [PMC free article] [PubMed] [Google Scholar]
[41].Alshammari T, Alshammari M, Nenov M, Hoxha E, Cambiaghi M, Marcinno A, et al. , 2016. Genetic deletion of fibroblast growth factor 14 recapitulates phenotypic alterations underlying cognitive impairment associated with schizophrenia. Transl Psychiatry 666. 10.1038/tp.2016.66. [DOI] [PMC free article] [PubMed] [Google Scholar]
[42].Bonaventura J, Eldridge MAG, Hu F, Gomez JL, Sanchez-Soto M, Abramyan AM, et al. , 2019. High-potency ligands for DREADD imaging and activation in rodents and monkeys. Nat Commun 10, 4627. 10.1038/s41467-019-12236-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
[43].Bolivar VJ, 2009. Intrasession and intersession habituation in mice: from inbred strain variability to linkage analysis. Neurobiol Learn Mem 92, 206–214. 10.1016/j.nlm.2009.02.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
[44].Di Gesù CM, Matz LM, Bolding IJ, Fultz R, Hoffman KL, Gammazza AM, et al. , 2022. Maternal gut microbiota mediate intergenerational effects of high-fat diet on descendant social behavior. Cell Rep 41, 111461. 10.1016/j.celrep.2022.111461. [DOI] [PMC free article] [PubMed] [Google Scholar]
[45].Rein B, Ma K, Yan Z, 2020. A standardized social preference protocol for measuring social deficits in mouse models of autism. Nat Protoc 15, 3464–3477. 10.1038/s41596-020-0382-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
[46].Lamsa K, Lau P, 2019. Long-term plasticity of hippocampal interneurons during in vivo memory processes. Curr Opin Neurobiol 54, 20–27. 10.1016/j.conb.2018.08.006. [DOI] [PubMed] [Google Scholar]
[47].Han S, Tai C, Westenbroek RE, Yu FH, Cheah CS, Potter GB, et al. , 2012. Autistic-like behaviour in Scn1a+ /− mice and rescue by enhanced GABA-mediated neurotransmission. Nature 489, 385–390. 10.1038/nature11356. [DOI] [PMC free article] [PubMed] [Google Scholar]
[48].Hanse E, Gustafsson B, 2001. Paired-pulse plasticity at the single release site level: an experimental and computational study. J Neurosci 21, 8362–8369. 10.1523/JNEUROSCI.21-21-08362.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
[49].Port RG, Oberman LM, Roberts TP, 2019. Revisiting the excitation/inhibition imbalance hypothesis of ASD through a clinical lens. Br J Radiol 92, 20180944. 10.1259/bjr.20180944. [DOI] [PMC free article] [PubMed] [Google Scholar]
[50].Han S, Tai C, Jones CJ, Scheuer T, Catterall WA, 2014. Enhancement of inhibitory neurotransmission by GABAA receptors having α2,3-subunits ameliorates behavioral deficits in a mouse model of autism. Neuron 81, 1282–1289. 10.1016/j.neuron.2014.01.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
[51].Naguy A, Pridmore S, Alamiri B, 2022. Benzodiazepines in autism spectrum disorder - Wise or otherwise? CNS Spectr 27, 552. 10.1017/S1092852921000481. [DOI] [PubMed] [Google Scholar]
[52].del Cerro S, Jung M, Lynch G, 1992. Benzodiazepines block long-term potentiation in slices of hippocampus and piriform cortex. Neuroscience 49, 1–6. 10.1016/0306-4522(92)90071-9. [DOI] [PubMed] [Google Scholar]
[53].Trinchero MF, Giacomini D, Schinder AF, 2021. Dynamic interplay between GABAergic networks and developing neurons in the adult hippocampus. Curr Opin Neurobiol 69, 124–130. 10.1016/j.conb.2021.03.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
[54].Pelkey KA, Chittajallu R, Craig MT, Tricoire L, Wester JC, McBain CJ, 2017. Hippocampal GABAergic inhibitory interneurons. Physiol Rev 97, 1619–1747. 10.1152/physrev.00007.2017. [DOI] [PMC free article] [PubMed] [Google Scholar]
[55].Urban DJ, Roth BL, 2014. DREADDs (Designer receptors exclusively activated by designer drugs): chemogenetic tools with therapeutic utility. Annu Rev Pharmacol Toxicol 55, 399–417. 10.1146/annurev-pharmtox-010814-124803. [DOI] [PubMed] [Google Scholar]
[56].Roth BL, 2016. DREADDs for neuroscientists. Neuron 89, 683–694. 10.1016/j.neuron.2016.01.040. [DOI] [PMC free article] [PubMed] [Google Scholar]
[57].Silverman JL, Yang M, Lord C, Crawley JN, 2010. Behavioural phenotyping assays for mouse models of autism. Nat Rev Neurosci 11, 490–502. 10.1038/nrn2851. [DOI] [PMC free article] [PubMed] [Google Scholar]
[58].Phillips ML, Robinson HA, Pozzo-Miller L, 2019. Ventral hippocampal projections to the medial prefrontal cortex regulate social memory. eLife 8. 10.7554/eLife.44182. [DOI] [PMC free article] [PubMed] [Google Scholar]
[59].Antunes M, Biala G, 2012. The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process 13, 93–110. 10.1007/s10339-011-0430-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
[60].Hossain MM, Belkadi A, Al-Haddad S, Richardson JR, 2020. Deltamethrin exposure inhibits adult hippocampal neurogenesis and causes deficits in learning and memory in mice. Toxicol Sci 178, 347–357. 10.1093/toxsci/kfaa144. [DOI] [PMC free article] [PubMed] [Google Scholar]
[61].Yang M, Silverman JL, Crawley JN, 2011. Automated three-chambered social approach task for mice. Curr Protoc Neurosci. 10.1002/0471142301.ns0826s56 (Chapter 8). [DOI] [PMC free article] [PubMed] [Google Scholar]
[62].Hao F, Bu Y, Huang S, Li W, Feng H, Wang Y, 2024. Maternal exposure to deltamethrin during pregnancy and lactation impairs neurodevelopment of male offspring. Ecotoxicol Environ Saf 274, 116196. 10.1016/j.ecoenv.2024.116196. [DOI] [PubMed] [Google Scholar]
[63].Solmi M, Song M, Yon DK, Lee SW, Fombonne E, Kim MS, et al. , 2022. Incidence, prevalence, and global burden of autism spectrum disorder from 1990 to 2019 across 204 countries. Mol Psychiatry 27, 4172–4180. 10.1038/s41380-022-01630-7. [DOI] [PubMed] [Google Scholar]
[64].Xia Y, Xia C, Jiang Y, Chen Y, Zhou J, Dai R, et al. , 2024. Transcriptomic sex differences in postmortem brain samples from patients with psychiatric disorders. Sci Transl Med 16, eadh9974. 10.1126/scitranslmed.adh9974. [DOI] [PubMed] [Google Scholar]
[65].Gochfeld M, 2017. Sex differences in human and animal toxicology. Toxicol Pathol 45, 172–189. 10.1177/0192623316677327. [DOI] [PMC free article] [PubMed] [Google Scholar]
[66].Gogolla N, Takesian AE, Feng G, Fagiolini M, Hensch TK, 2014. Sensory integration in mouse insular cortex reflects GABA circuit maturation. Neuron 83, 894–905. 10.1016/j.neuron.2014.06.033. [DOI] [PMC free article] [PubMed] [Google Scholar]
[67].Hossain MM, Suzuki T, Unno T, Komori S, Kobayashi H, 2008. Differential presynaptic actions of pyrethroid insecticides on glutamatergic and GABAergic neurons in the hippocampus. Toxicology 243, 155–163. 10.1016/j.tox.2007.10.003. [DOI] [PubMed] [Google Scholar]
[68].Lee E, Lee J, Kim E, 2017. Excitation/inhibition imbalance in animal models of autism spectrum disorders. Biol Psychiatry 81, 838–847. 10.1016/j.biopsych.2016.05.011. [DOI] [PubMed] [Google Scholar]
[69].Zarnadze S, Bäuerle P, Santos-Torres J, Böhm C, Schmitz D, Geiger JR, et al. , 2016. Cell-specific synaptic plasticity induced by network oscillations. eLife 5. 10.7554/eLife.14912. [DOI] [PMC free article] [PubMed] [Google Scholar]
[70].Bikbaev A, 2008. D. Manahan-Vaughan, Relationship of hippocampal theta and gamma oscillations to potentiation of synaptic transmission. Front Neurosci 2, 56–63. 10.3389/neuro.01.010.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
[71].Mi D, Li Z, Lim L, Li M, Moissidis M, Yang Y, et al. , 2018. Early emergence of cortical interneuron diversity in the mouse embryo. Science 360, 81–85. 10.1126/science.aar6821. [DOI] [PMC free article] [PubMed] [Google Scholar]
[72].American Psychiatric Association, 2022. Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Association Publishing. 10.1176/appi.books.9780890425787. [DOI] [Google Scholar]
[73].Zou D, Chen L, Deng D, Jiang D, Dong F, McSweeney C, et al. , 2016. DREADD in parvalbumin interneurons of the dentate gyrus modulates anxiety, social interaction and memory extinction. Curr Mol Med 16, 91–102. 10.3171/jns.1971.34.6.0827. [DOI] [PMC free article] [PubMed] [Google Scholar]
[74].Pitzer EM, Williams MT, Vorhees CV, 2021. Effects of pyrethroids on brain development and behavior: deltamethrin. Neurotoxicol Teratol 87, 106983. 10.1016/j.ntt.2021.106983. [DOI] [PMC free article] [PubMed] [Google Scholar]
[75].Ogut E, Sekerci R, Akcay G, Yildirim FB, Derin N, Aslan M, et al. , 2019. Protective effects of syringic acid on neurobehavioral deficits and hippocampal tissue damages induced by sub-chronic deltamethrin exposure. Neurotoxicol Teratol 76, 106839. 10.1016/j.ntt.2019.106839. [DOI] [PubMed] [Google Scholar]

Associated Data

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

Supplementary Materials

Supplementary Material

NIHMS2063442-supplement-Supplementary_Material.pdf^{(702.6KB, pdf)}

Data Availability Statement

Data will be made available on request.

[R1] [1].GBD 2021 Nervous System Disorders Collaborators, 2024. Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the global burden of disease study 2021. Lancet Neurol 23, 344–381. 10.1016/S1474-4422(24)00038-3. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R2] [2].Krause S, Ouellet V, Allen D, Allen S, Moss K, Nel HA, et al. , 2024. The potential of micro- and nanoplastics to exacerbate the health impacts and global burden of non-communicable diseases. Cell Rep Med 5, 101581. 10.1016/j.xcrm.2024.101581. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R3] [3].Lipkin WI, Bresnahan M, Susser E, 2023. Cohort-guided insights into gene-environment interactions in autism spectrum disorders. Nat Rev Neurol 19, 118–125. 10.1038/s41582-022-00764-0. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R4] [4].Schwabe I, Jović M, Rimfeld K, Allegrini AG, van den Berg SM, 2024. Genotype-environment interaction in ADHD: genetic predisposition determines the extent to which environmental influences explain variability in the symptom dimensions hyperactivity and inattention. Behav Genet 54, 169–180. 10.1007/s10519-023-10168-5. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R5] [5].Sly PD, Flack F, 2008. Susceptibility of children to environmental pollutants. Ann N Y Acad Sci 1140, 163–183. 10.1196/annals.1454.017. [DOI] [PubMed] [Google Scholar]

[R6] [6].Hauptman M, Woolf AD, 2017. Childhood ingestions of environmental toxins: what are the risks? e466–e471 Pediatr Ann 46. 10.3928/19382359-20171116-01. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R7] [7].Amaraneni M, Pang J, Mortuza TB, Muralidhara S, Cummings BS, White CA, et al. , 2017. Brain uptake of deltamethrin in rats as a function of plasma protein binding and blood-brain barrier maturation. Neurotoxicology 62, 24–29. 10.1016/j.neuro.2017.04.009. [DOI] [PubMed] [Google Scholar]

[R8] [8].Meacham CA, Brodfuehrer PD, Watkins JA, Shafer TJ, 2008. Developmentally-regulated sodium channel subunits are differentially sensitive to alpha-cyano containing pyrethroids. Toxicol Appl Pharmacol 231, 273–281. 10.1016/j.taap.2008.04.017. [DOI] [PubMed] [Google Scholar]

[R9] [9].Kim K-B, Anand SS, Kim HJ, White CA, Fisher JW, Tornero-Velez R, et al. , 2010. Age, dose, and time-dependency of plasma and tissue distribution of deltamethrin in immature rats. Toxicol Sci 115, 354–368. 10.1093/toxsci/kfq074. [DOI] [PubMed] [Google Scholar]

[R10] [10].Macheka LR, Palazzi P, Iglesias-González A, Zaros C, Appenzeller BMR, Zeman FA, 2024. Exposure to pesticides, persistent and non - persistent pollutants in French 3.5-year-old children: findings from comprehensive hair analysis in the ELFE national birth cohort. Environ Int 190, 108881. 10.1016/j.envint.2024.108881. [DOI] [PubMed] [Google Scholar]

[R11] [11].Béranger R, Hardy EM, Binter A-C, Charles M-A, Zaros C, Appenzeller BMR, et al. , 2020. Multiple pesticides in mothers’ hair samples and children’s measurements at birth: results from the French national birth cohort (ELFE). Int J Hyg Environ Health 223, 22–33. 10.1016/j.ijheh.2019.10.010. [DOI] [PubMed] [Google Scholar]

[R12] [12].Viel J-F, Rouget F, Warembourg C, Monfort C, Limon G, Cordier S, et al. , 2017. Behavioural disorders in 6-year-old children and pyrethroid insecticide exposure: the PELAGIE mother-child cohort. Occup Environ Med 74, 275–281. 10.1136/oemed-2016-104035. [DOI] [PubMed] [Google Scholar]

[R13] [13].Viel J-F, Warembourg C, Le Maner-Idrissi G, Lacroix A, Limon G, Rouget F, et al. , 2015. Pyrethroid insecticide exposure and cognitive developmental disabilities in children: the PELAGIE mother-child cohort. Environ Int 82, 69–75. 10.1016/j.envint.2015.05.009. [DOI] [PubMed] [Google Scholar]

[R14] [14].Richardson JR, Taylor MM, Shalat SL, Guillot TS, Caudle WM, Hossain MM, et al. , 2015. Developmental pesticide exposure reproduces features of attention deficit hyperactivity disorder. FASEB J 29, 1960–1972. 10.1096/fj.14-260901. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R15] [15].Pitzer EM, Sugimoto C, Regan SL, Gudelsky GA, Williams MT, Vorhees CV, 2022. Developmental deltamethrin: sex-specific hippocampal effects in Sprague Dawley rats. Curr Res Toxicol 3, 100093. 10.1016/j.crtox.2022.100093. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R16] [16].Jiménez JA, Simon JM, Hu W, Moy SS, Harper KM, Liu CW, et al. , 2022. Developmental pyrethroid exposure and age influence phenotypes in a Chd8 haploinsufficient autism mouse model. Sci Rep 12, 1–15. 10.1038/s41598-022-09533-x. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R17] [17].Curtis MA, Dhamsania RK, Branco RC, Guo J-D, Creeden J, Neifer KL, et al. , 2023. Developmental pyrethroid exposure causes a neurodevelopmental disorder phenotype in mice. PNAS Nexus 2, pgad085. 10.1093/pnasnexus/pgad085. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R18] [18].Deltamethrin USEPA, 2004. Pesticide tolerance. Fed Regist 69, 62602–62615. [Google Scholar]

[R19] [19].Vermeulen R, Schymanski EL, Barabási A-L, Miller GW, 2020. The exposome and health: where chemistry meets biology. Science 367, 392–396. 10.1126/science.aay3164. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R20] [20].Field LM, Davies TGE, O’Reilly AO, Williamson MS, Wallace BA, 2017. Voltage-gated sodium channels as targets for pyrethroid insecticides. Eur Biophys J 46, 675–679. 10.1007/s00249-016-1195-1. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R21] [21].James TF, Nenov MN, Tapia CM, Lecchi M, Koshy S, Green TA, et al. , 2017. Consequences of acute Nav1.1 exposure to deltamethrin. Neurotoxicology 60, 150–160. 10.1016/j.neuro.2016.12.005. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R22] [22].Abráhám H, Kojima H, Götzer K, Molnár A, Tornóczky T, Seress L, 2023. Development of parvalbumin-immunoreactive neurons in the postnatal human hippocampal formation. Front Neuroanat 17, 1058370. 10.3389/fnana.2023.1058370. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R23] [23].Rexrode LE, Hartley J, Showmaker KC, Challagundla L, Vandewege MW, Martin BE, et al. , 2024. Molecular profiling of the hippocampus of children with autism spectrum disorder. Mol Psychiatry 1–12. 10.1038/s41380-024-02441-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R24] [24].Neufeld J, Maier S, Revers M, Reisert M, Kuja-Halkola R, Tebartz van Elst L, et al. , 2023. Reduced brain connectivity along the autism spectrum controlled for familial confounding by co-twin design. Sci Rep 13, 13124. 10.1038/s41598-023-39876-y. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R25] [25].Bezaire MJ, Soltesz I, 2013. Quantitative assessment of CA1 local circuits: knowledge base for interneuron-pyramidal cell connectivity. Hippocampus 23, 751–785. 10.1002/hipo.22141. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R26] [26].Khlaifia A, Honoré E, Artinian J, Laplante I, Lacaille JC, 2022. mTORC1 function in hippocampal parvalbumin interneurons: regulation of firing and long-term potentiation of intrinsic excitability but not long-term contextual fear memory and context discrimination. Mol Brain 15, 1–16. 10.1186/s13041-022-00941-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R27] [27].Campanac E, Gasselin C, Baude A, Rama S, Ankri N, Debanne D, 2013. Enhanced intrinsic excitability in basket cells maintains excitatory-inhibitory balance in hippocampal circuits. Neuron 77, 712–722. 10.1016/j.neuron.2012.12.020. [DOI] [PubMed] [Google Scholar]

[R28] [28].Deng X, Gu L, Sui N, Guo J, Liang J, 2019. Parvalbumin interneuron in the ventral hippocampus functions as a discriminator in social memory. Proc Natl Acad Sci USA 116, 16583–16592. 10.1073/pnas.1819133116. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R29] [29].Okuyama T, Kitamura T, Roy DS, Itohara S, Tonegawa S, 2016. Ventral CA1 neurons store social memory. Science 353, 1536–1541. 10.1126/science.aaf7003. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R30] [30].Tao K, Chung M, Watarai A, Huang Z, Wang MY, Okuyama T, 2022. Disrupted social memory ensembles in the ventral hippocampus underlie social amnesia in autism-associated Shank3 mutant mice. Mol Psychiatry 27, 2095–2105. 10.1038/s41380-021-01430-5. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R31] [31].Paterno R, Marafiga JR, Ramsay H, Li T, Salvati KA, Baraban SC, 2021. Hippocampal gamma and sharp-wave ripple oscillations are altered in a Cntnap2 mouse model of autism spectrum disorder. Cell Rep 37, 109970. 10.1016/j.celrep.2021.109970. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R32] [32].Selby L, Zhang C, Sun Q-Q, 2007. Major defects in neocortical GABAergic inhibitory circuits in mice lacking the fragile X mental retardation protein. Neurosci Lett 412, 227–232. 10.1016/j.neulet.2006.11.062. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R33] [33].Gogolla N, Leblanc JJ, Quast KB, Südhof TC, Fagiolini M, Hensch TK, 2009. Common circuit defect of excitatory-inhibitory balance in mouse models of autism. J Neurodev Disord 1, 172–181. 10.1007/s11689-009-9023-x. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R34] [34].Filice F, Janickova L, Henzi T, Bilella A, Schwaller B, 2020. The parvalbumin hypothesis of autism spectrum disorder. Front Cell Neurosci 14, 577525. 10.3389/fncel.2020.577525. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R35] [35].Juarez P, Martínez Cerdeño V, 2022. Parvalbumin and parvalbumin chandelier interneurons in autism and other psychiatric disorders. Front Psychiatry 13, 913550. 10.3389/fpsyt.2022.913550. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R36] [36].Tatsukawa T, Ogiwara I, Mazaki E, Shimohata A, Yamakawa K, 2018. Impairments in social novelty recognition and spatial memory in mice with conditional deletion of Scn1a in parvalbumin-expressing cells. Neurobiol Dis 112, 24–34. 10.1016/j.nbd.2018.01.009. [DOI] [PubMed] [Google Scholar]

[R37] [37].Robbe D, Kopf M, Remaury A, Bockaert J, Manzoni OJ, 2002. Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens. Proc Natl Acad Sci USA 99, 8384–8388. 10.1073/pnas.122149199. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R38] [38].Schramm NL, Egli RE, Winder DG, 2002. LTP in the mouse nucleus accumbens is developmentally regulated. Synapse 45, 213–219. 10.1002/syn.10104. [DOI] [PubMed] [Google Scholar]

[R39] [39].Stein RE, Kaplan JS, Li J, Catterall WA, 2019. Hippocampal deletion of NaV1.1 channels in mice causes thermal seizures and cognitive deficit characteristic of Dravet syndrome. Proc Natl Acad Sci USA 116, 16571–16576. 10.1073/pnas.1906833116. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R40] [40].Krashes MJ, Koda S, Ye C, Rogan SC, Adams AC, Cusher DS, et al. , 2011. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J Clin Investig 121, 1424–1428. 10.1172/JCI46229. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R41] [41].Alshammari T, Alshammari M, Nenov M, Hoxha E, Cambiaghi M, Marcinno A, et al. , 2016. Genetic deletion of fibroblast growth factor 14 recapitulates phenotypic alterations underlying cognitive impairment associated with schizophrenia. Transl Psychiatry 666. 10.1038/tp.2016.66. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R42] [42].Bonaventura J, Eldridge MAG, Hu F, Gomez JL, Sanchez-Soto M, Abramyan AM, et al. , 2019. High-potency ligands for DREADD imaging and activation in rodents and monkeys. Nat Commun 10, 4627. 10.1038/s41467-019-12236-z. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R43] [43].Bolivar VJ, 2009. Intrasession and intersession habituation in mice: from inbred strain variability to linkage analysis. Neurobiol Learn Mem 92, 206–214. 10.1016/j.nlm.2009.02.002. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R44] [44].Di Gesù CM, Matz LM, Bolding IJ, Fultz R, Hoffman KL, Gammazza AM, et al. , 2022. Maternal gut microbiota mediate intergenerational effects of high-fat diet on descendant social behavior. Cell Rep 41, 111461. 10.1016/j.celrep.2022.111461. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R45] [45].Rein B, Ma K, Yan Z, 2020. A standardized social preference protocol for measuring social deficits in mouse models of autism. Nat Protoc 15, 3464–3477. 10.1038/s41596-020-0382-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R46] [46].Lamsa K, Lau P, 2019. Long-term plasticity of hippocampal interneurons during in vivo memory processes. Curr Opin Neurobiol 54, 20–27. 10.1016/j.conb.2018.08.006. [DOI] [PubMed] [Google Scholar]

[R47] [47].Han S, Tai C, Westenbroek RE, Yu FH, Cheah CS, Potter GB, et al. , 2012. Autistic-like behaviour in Scn1a+ /− mice and rescue by enhanced GABA-mediated neurotransmission. Nature 489, 385–390. 10.1038/nature11356. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R48] [48].Hanse E, Gustafsson B, 2001. Paired-pulse plasticity at the single release site level: an experimental and computational study. J Neurosci 21, 8362–8369. 10.1523/JNEUROSCI.21-21-08362.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R49] [49].Port RG, Oberman LM, Roberts TP, 2019. Revisiting the excitation/inhibition imbalance hypothesis of ASD through a clinical lens. Br J Radiol 92, 20180944. 10.1259/bjr.20180944. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R50] [50].Han S, Tai C, Jones CJ, Scheuer T, Catterall WA, 2014. Enhancement of inhibitory neurotransmission by GABAA receptors having α2,3-subunits ameliorates behavioral deficits in a mouse model of autism. Neuron 81, 1282–1289. 10.1016/j.neuron.2014.01.016. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R51] [51].Naguy A, Pridmore S, Alamiri B, 2022. Benzodiazepines in autism spectrum disorder - Wise or otherwise? CNS Spectr 27, 552. 10.1017/S1092852921000481. [DOI] [PubMed] [Google Scholar]

[R52] [52].del Cerro S, Jung M, Lynch G, 1992. Benzodiazepines block long-term potentiation in slices of hippocampus and piriform cortex. Neuroscience 49, 1–6. 10.1016/0306-4522(92)90071-9. [DOI] [PubMed] [Google Scholar]

[R53] [53].Trinchero MF, Giacomini D, Schinder AF, 2021. Dynamic interplay between GABAergic networks and developing neurons in the adult hippocampus. Curr Opin Neurobiol 69, 124–130. 10.1016/j.conb.2021.03.008. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R54] [54].Pelkey KA, Chittajallu R, Craig MT, Tricoire L, Wester JC, McBain CJ, 2017. Hippocampal GABAergic inhibitory interneurons. Physiol Rev 97, 1619–1747. 10.1152/physrev.00007.2017. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R55] [55].Urban DJ, Roth BL, 2014. DREADDs (Designer receptors exclusively activated by designer drugs): chemogenetic tools with therapeutic utility. Annu Rev Pharmacol Toxicol 55, 399–417. 10.1146/annurev-pharmtox-010814-124803. [DOI] [PubMed] [Google Scholar]

[R56] [56].Roth BL, 2016. DREADDs for neuroscientists. Neuron 89, 683–694. 10.1016/j.neuron.2016.01.040. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R57] [57].Silverman JL, Yang M, Lord C, Crawley JN, 2010. Behavioural phenotyping assays for mouse models of autism. Nat Rev Neurosci 11, 490–502. 10.1038/nrn2851. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R58] [58].Phillips ML, Robinson HA, Pozzo-Miller L, 2019. Ventral hippocampal projections to the medial prefrontal cortex regulate social memory. eLife 8. 10.7554/eLife.44182. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R59] [59].Antunes M, Biala G, 2012. The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process 13, 93–110. 10.1007/s10339-011-0430-z. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R60] [60].Hossain MM, Belkadi A, Al-Haddad S, Richardson JR, 2020. Deltamethrin exposure inhibits adult hippocampal neurogenesis and causes deficits in learning and memory in mice. Toxicol Sci 178, 347–357. 10.1093/toxsci/kfaa144. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R61] [61].Yang M, Silverman JL, Crawley JN, 2011. Automated three-chambered social approach task for mice. Curr Protoc Neurosci. 10.1002/0471142301.ns0826s56 (Chapter 8). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R62] [62].Hao F, Bu Y, Huang S, Li W, Feng H, Wang Y, 2024. Maternal exposure to deltamethrin during pregnancy and lactation impairs neurodevelopment of male offspring. Ecotoxicol Environ Saf 274, 116196. 10.1016/j.ecoenv.2024.116196. [DOI] [PubMed] [Google Scholar]

[R63] [63].Solmi M, Song M, Yon DK, Lee SW, Fombonne E, Kim MS, et al. , 2022. Incidence, prevalence, and global burden of autism spectrum disorder from 1990 to 2019 across 204 countries. Mol Psychiatry 27, 4172–4180. 10.1038/s41380-022-01630-7. [DOI] [PubMed] [Google Scholar]

[R64] [64].Xia Y, Xia C, Jiang Y, Chen Y, Zhou J, Dai R, et al. , 2024. Transcriptomic sex differences in postmortem brain samples from patients with psychiatric disorders. Sci Transl Med 16, eadh9974. 10.1126/scitranslmed.adh9974. [DOI] [PubMed] [Google Scholar]

[R65] [65].Gochfeld M, 2017. Sex differences in human and animal toxicology. Toxicol Pathol 45, 172–189. 10.1177/0192623316677327. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R66] [66].Gogolla N, Takesian AE, Feng G, Fagiolini M, Hensch TK, 2014. Sensory integration in mouse insular cortex reflects GABA circuit maturation. Neuron 83, 894–905. 10.1016/j.neuron.2014.06.033. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R67] [67].Hossain MM, Suzuki T, Unno T, Komori S, Kobayashi H, 2008. Differential presynaptic actions of pyrethroid insecticides on glutamatergic and GABAergic neurons in the hippocampus. Toxicology 243, 155–163. 10.1016/j.tox.2007.10.003. [DOI] [PubMed] [Google Scholar]

[R68] [68].Lee E, Lee J, Kim E, 2017. Excitation/inhibition imbalance in animal models of autism spectrum disorders. Biol Psychiatry 81, 838–847. 10.1016/j.biopsych.2016.05.011. [DOI] [PubMed] [Google Scholar]

[R69] [69].Zarnadze S, Bäuerle P, Santos-Torres J, Böhm C, Schmitz D, Geiger JR, et al. , 2016. Cell-specific synaptic plasticity induced by network oscillations. eLife 5. 10.7554/eLife.14912. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R70] [70].Bikbaev A, 2008. D. Manahan-Vaughan, Relationship of hippocampal theta and gamma oscillations to potentiation of synaptic transmission. Front Neurosci 2, 56–63. 10.3389/neuro.01.010.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R71] [71].Mi D, Li Z, Lim L, Li M, Moissidis M, Yang Y, et al. , 2018. Early emergence of cortical interneuron diversity in the mouse embryo. Science 360, 81–85. 10.1126/science.aar6821. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R72] [72].American Psychiatric Association, 2022. Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Association Publishing. 10.1176/appi.books.9780890425787. [DOI] [Google Scholar]

[R73] [73].Zou D, Chen L, Deng D, Jiang D, Dong F, McSweeney C, et al. , 2016. DREADD in parvalbumin interneurons of the dentate gyrus modulates anxiety, social interaction and memory extinction. Curr Mol Med 16, 91–102. 10.3171/jns.1971.34.6.0827. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R74] [74].Pitzer EM, Williams MT, Vorhees CV, 2021. Effects of pyrethroids on brain development and behavior: deltamethrin. Neurotoxicol Teratol 87, 106983. 10.1016/j.ntt.2021.106983. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R75] [75].Ogut E, Sekerci R, Akcay G, Yildirim FB, Derin N, Aslan M, et al. , 2019. Protective effects of syringic acid on neurobehavioral deficits and hippocampal tissue damages induced by sub-chronic deltamethrin exposure. Neurotoxicol Teratol 76, 106839. 10.1016/j.ntt.2019.106839. [DOI] [PubMed] [Google Scholar]

PERMALINK

Environmental exposure to common pesticide induces synaptic deficit and social memory impairment driven by neurodevelopmental vulnerability of hippocampal parvalbumin interneurons

Jessica Di Re

Leandra Koff

Yosef Avchalumov

Aditya K Singh

Timothy J Baumgartner

Mate Marosi

Lisa M Matz

Lance M Hallberg

Bill T Ameredes

Erin H Seeley

Shelly A Buffington

Thomas A Green

Fernanda Laezza

Abstract

Graphical Abstract

1. Introduction

2. Materials and methods

2.1. Dosing

2.2. Evoked extracellular field potential recordings

Fig. 1.

Fig. 2.

Fig. 4.

2.3. Stereotaxic Surgery

2.4. Whole-cell patch clamp recordings in current clamp mode

Fig. 3.

2.5. Whole-cell patch clamp recordings in voltage clamp mode

2.6. MALDI imaging

2.7. Immunohistochemistry

2.8. Confocal imaging

2.9. Open field testing (OFT)

2.10. Novel object recognition (NOR)

2.11. Sociability and preference for social novelty testing

2.12. Statistical analysis

3. Results

3.1. Disrupted hippocampal GABAergic signaling induced by maternal DM exposure

3.2. DM-induced changes in GABAergic signaling are rescued by chemogenetic activation of PV interneuron firing

3.3. Maternal DM exposure impairs PV interneuron-dependent social memory

Fig. 5.

Fig. 6.

4. Discussion

5. Conclusion

Environmental implications

Supplementary Material

HIGHLIGHTS.

Funding

Footnotes

Data availability

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases