Table 1.
Studies evaluating neuronal network excitability in hAPP/Aβ mouse models of AD
| Author(s) and publication year | Mouse model/transgene(s)/promoter | Age/stage of pathology | Neuronal network excitability status | Experimental paradigm/neuronal network excitability observation(s) |
|---|---|---|---|---|
| Studies assessing neuronal network hyperexcitability in hAPP/Aβ mice at advanced stages of Aβ plaque pathology and cognitive impairment | ||||
| Palop et al. (2007) | hAPP-J20 (hAPP Swedish and Indiana) PDGF-β promoter |
4–7 months, Aβ plaques deposition, cognitive impairment, synaptic deficit | Increased | Experimental paradigm: in vivo chronic video EEG recordings; PTZ-induced seizure susceptibility; in vitro mIPSCs and fEPSPs recordings. Findings: frequent epileptiform activity including spikes and SWDs and increased PTZ-induced seizure susceptibility in hAPP-J20 mice. Reduced LTP and PPF in hippocampal perforant pathway in hAPP-J20 mice slices. Increased dentate granule cells mIPSCs frequency in hAPP-J20 mice. Remodeling of inhibitory circuits and altered NPY expression in dentate gyrus of hAPP-J20 mice. |
| Verret et al. (2012) | hAPP-J20 (hAPP Swedish and Indiana) PDGF-β promoter |
4–7 months, Aβ plaques deposition, cognitive impairment, synaptic deficit | Increased | Experimental paradigm: in vivo chronic video EEG recordings. Findings: spontaneous epileptiform discharges observed during reduced γ oscillatory activity (generated by inhibitory PV cells) in hAPP-J20 mice. Decreased levels of the interneuron-specific and PV cell-predominant voltage-gated sodium channel subunit Nav1.1. Restoring Nav1.1 level in hAPP-J20 mice increased inhibitory synaptic activity and γ oscillations and reduced hyperexcitability and cognitive deficits. |
| Sanchez et al. (2012) | hAPP-J20 (hAPP Swedish and Indiana) PDGF-β promoter |
4–6 months, Aβ plaques deposition, cognitive impairment, synaptic deficit | Increased | Experimental paradigm: in vivo chronic video EEG recordings; fEPSPs in acute hippocampal slices. Findings: spontaneous epileptiform activity in hAPP-J20 mice. Chronic treatment with levetiracetam reversed abnormal spiking activity, hippocampal remodeling, behavioral abnormalities, synaptic dysfunction, and deficits in learning and memory in hAPP-J20 mice. |
| Martinez-Losa et al. (2018) | hAPP-J20 (hAPP Swedish and Indiana) PDGF-β promoter |
7–8 months, Aβ plaques deposition, cognitive impairment, synaptic deficit | Increased | Experimental paradigm: in vivo EEG recordings in freely moving mice. Findings: epileptiform spikes on cortical EEG in hAPP-J20 mice. Nav1.1-overexpressing, interneuron transplants enhanced reduced network hypersynchrony and improved cognitive functions in hAPP-J20 mice. |
| Minkeviciene et al. (2009) | APdE9 (hAPP Swedish and PSEN1: deltaE9) Prp promoter |
3 and 4.5 months, substantial number Aβ plaques observed in cortex, hippocampus, and amygdala | Increased | Experimental paradigm: in vivo video EEG recordings; patch clamp electrophysiology; extracellular field recordings in brain slices. Findings: unprovoked seizures in APdE9 mice. Hyperexcitability in neocortical layer 2/3 pyramidal cells in APdE9 mice on patch clamp recordings. Aβ protofibrils induced neuronal network hyperexcitability in acute brain slices. |
| Ziyatdinova et al. (2011) | APdE9 (hAPP Swedish and PSEN1: deltaE9) Prp promoter |
4–5 months, Aβ plaques in the neocortex and hippocampus | Increased | Experimental paradigm: in vivo video EEG recordings. Findings: spontaneous electrographic epileptiform discharges. Antiepileptic drugs that block sodium chan-nels, including carbamazepine, phenytoin, and valproic acid suppressed epileptiform activity in APdE9 mice with increased amyloid pathology. |
| Gurevicius et al. (2013) | APdE9 (hAPP Swedish and PSEN1: deltaE9) Prp promoter |
4 months; Aβ plaques in the neocortex and hippocampus | Increased | Experimental paradigm: in vivo EEG recordings from the hippocampus, cerebral cortex, and thalamus during movement, quiet waking, non-rapid eye movement sleep, and REM sleep. Findings: cortical EEG power was higher in APdE9 mice than in WT mice over a broad frequency range (5–100 Hz) and during all 4 behavioral states. Thalamic EEG power was also increased but in a narrower range (10–80 Hz). While power and θ–γ modulation were preserved in the APdE9 hippocampus, REM sleep-related phase shift of θ–γ modulation was altered. |
| Ziyatdinova et al. (2015) | APdE9 (hAPP Swedish and PSEN1: deltaE9) Prp promoter |
4–5 months, Aβ plaques in the neocortex and hippocampus | Increased | Experimental paradigm: in vivo video EEG recordings. Findings: spontaneous epileptiform discharges. Antiepileptic drug valproic acid reduced the amount of epileptiform activity, but the effect disappeared after treatment discontinuation. |
| Nygaard et al. (2015) | APdE9 (hAPP Swedish and PSEN1: deltaE9) Prp promoter |
10 months, Aβ plaques in the cortex and hippocampus | Increased | Experimental paradigm: in vivo video EEG recordings. Findings: epileptiform activity in the form of SWDs in APdE9 mice. SWDs correlated with spatial memory impairment in these mice. Brivaracetam (a chemical analog of levetiracetam) reduced SWDs and reversed memory impairments in in APdE9 mice. |
| Reyes-Marin and Nuñez (2017) | APdE9 (hAPP Swedish and PSEN1: deltaE9) Prp promoter |
4–9 months, Aβ plaques in the cortex and hippocampus | Increased | Experimental paradigm: in vivo video EEG recordings; PTZ-induced seizure susceptibility. Findings: higher incidence of epileptiform-like discharges, i.e., seizure events (interictal spikes, sharp waves, or polyspikes) in APdE9 than in the controls. Also, APdE9 mice showed a lower latency to PTZ-evoked seizure events than in the control animals. A correlation was also found between the frequency of epileptiform-like discharges and the number of Aβ plaques. |
| Busche et al. (2008) | APP23xPS45 (hAPP751 Swedish and PSEN1-Gly384→Ala384, G384A) Thy-1 promoter |
8–10 months, Aβ plaques | Increased | Experimental paradigm: in vivo two-photon Ca2+ imaging of neurons in layer 2/3 of the cortex. Findings: clusters of hyperactive neurons were found in the vicinity of Aβ plaques. |
| Busche et al. (2012) | APP23xPS45 (hAPP751 Swedish and PSEN1-Gly384→Ala384, G384A) Thy-1 promoter |
6–7 months, Aβ plaques | Increased | Experimental paradigm: in vivo two-photon Ca2+ imaging of CA1 pyramidal neurons in the hippocampus. Findings: hyperactive neurons were found to be located exclusively in the vicinity of Aβ plaques in the hippocampus of transgenic mice. |
| Lalonde et al. (2005) | APP23 (hAPP751 Swedish) Thy-1 promoter |
24 months, Aβ plaques | Increased | Experimental paradigm: behavioral seizures evaluation. Findings: 41% of APP23 mice exhibited tonic-clonic seizures; 24% displayed myoclonic jumping. |
| Jolas et al. (2002) | TgCRND8 (hAPP695 Swedish and Indiana) Prp promoter |
5 months, Aβ plaques | Increased | Experimental paradigm: in vitro hippocampal electrophysiology recordings; evoked EPSCs and IPSCs; PTZ-induced seizure threshold. Findings: increased synaptic excitability and increased maximum amplitude of evoked mEPSCs; consistently lower dose of PTZ was required to elicit myoclonic activity (preseizure signs) in TgCRND8 mice compared with controls. |
| Siwek et al. (2015) | 5XFAD (hAPP Swedish, Florida, and London plus PSEN1: M146L and L286V) Thy-1 promoter |
16.5 months, Aβ plaques throughout hippocampus and cortex | Increased | Experimental paradigm: in vivo video EEG recordings from the cortex and the hippocampus. Findings: aberrant hyperexcitability in 5×FAD mice evidenced as ictal-like discharges, such as spikes, polyspikes, and spike-waves. |
| Davis et al. (2014) | 3xTg-AD (hAPP Swedish. htau P301L, and hPSEN1: M146V) Thy-1.2 promoter |
17–18 months, Aβ plaques | Increased | Experimental paradigm: in vivo hippocampal electrophysiology recordings. Findings: increased synaptic excitability in DG and CA1. |
| Nygaard et al. (2015) | 3xTg-AD (hAPP Swedish. htau P301L, and hPSEN1: M146V) Thy-1.2 promoter |
8–10 months, Aβ plaques, cognitive impairment | Increased | Experimental paradigm: in vivo video EEG recordings from the cortex. Findings: SWDs in 3×Tg-AD mice which correlated with spatial memory impairments. |
| Chan et al. (2015) | Tg2576 (hAPP Swedish), Prp promoter |
12–14 months, Aβ plaques, cognitive impairment | Increased | Experimental paradigm: electrical amygdala kindling with implanted electrodes and behavioral seizures evaluation. Findings: Tg2576 mice exhibited increased susceptibility to kindling and seizure-associated death. |
| Studies evaluating neuronal network hyperexcitability in hAPP/Aβ mice at early stages of Aβ pathology before plaque deposition and/or cognitive impairment | ||||
| Westmark et al. (2008) | Tg2576 (hAPP Swedish), Prp promoter |
2 months, before Aβ plaques deposition and cognitive impairment | Increased | Experimental paradigm: PTZ-induced seizure susceptibility assessment. Findings: increased susceptibility to PTZ-induced seizures in Tg2576 mice. |
| Westmark et al. (2010) | Tg2576 (hAPP Swedish), Prp promoter |
3 weeks, before Aβ plaques deposition and cognitive impairment | Increased | Experimental paradigm: audiogenic seizure susceptibility evaluation. Findings: increased susceptibility to audiogenic seizures in Tg2576 mice as compared with WT controls. The audiogenic seizure susceptibility in Tg2576 mice could be suppressed by passive immunization with an anti-APP/Aβ antibody or by blockade of mGluR5 with the selective antagonist, MPEP. |
| Corbett et al. (2013) | Tg2576 (hAPP Swedish), Prp promoter |
5–7 months, before Aβ plaques deposition | Increased | Experimental paradigm: in vivo EEG recordings. Findings: presence of SWDs and abnormal EEG patterns in Tg2576 mice; these mice also exhibited longer durations of higher frequency brain activity, suggesting increased synchrony. |
| Bezzina et al. (2015) | Tg2576 (hAPP Swedish), Prp promoter |
1.5–2 months, before Aβ plaques deposition and cognitive impairment | Increased | Experimental paradigm: electrical amygdala kindling with implanted electrodes and behavioral seizures evaluation. Findings: Tg2576 mice exhibited increased susceptibility to kindling and seizure-associated death. |
| Duffy et al. (2015) | Tg2576 (hAPP Swedish), Prp promoter |
2–4 months, prior to Aβ plaques deposition; soluble Aβ40 and Aβ42 detectable; impairment in object location, an EC-dependent cognitive task. | Increased | Experimental paradigm: ex vivo EC recordings. Findings: increased excitability in EC recordings in slices from Tg2576 mice. |
| Kam et al. (2016) | Tg2576 (hAPP Swedish), Prp promoter |
5 weeks, prior to Aβ plaques deposition and cognitive impairment | Increased | Experimental paradigm: in vivo video EEG recordings. Findings: synchronized large amplitude potentials resembling interictal spikes in epilepsy were observed in Tg2576 mice. |
| Ciccone et al. (2019) | Tg2576 (hAPP Swedish), Prp promoter |
3 months, before Aβ plaques deposition | Increased | Experimental paradigm: extracellular fEPSP activity elicited by the proconvulsant drug 4-aminopyridine (4-AP) in acute hippocampal slices from 3-month-old WT and Tg2576 slices. Findings: significantly higher number of electrical discharges, occurring with similar amplitude but shorter intervals, was observed in Tg2576 in comparison to WT hippocampal slices after 4-AP application. |
| Del Vecchio et al. (2004) | TgCRND8 (hAPP695 Swedish and Indiana) Prp promoter |
6–8 weeks, before Aβ plaques deposition | Increased | Experimental paradigm: PTZ-induced seizure susceptibility evaluation. Findings: increased susceptibility to PTZ-induced seizures in TgCRND8 mice. |
| Fontana et al. (2017) | PS2APP (hAPP Swedish and hPSEN2: N141I) Thy1 (hAPP) and Prp(hPSEN2) promoters |
3 months, before Aβ plaques deposition and cognitive impairment | Increased | Experimental paradigm: in vivo spontaneous LFPs in DG. Findings: network hypersynchronicity was observed in the DG of PS2APP mice. |
| Busche et al. (2012) | APP23xPS45 (hAPP751 Swedish and PSEN1-Gly384→Ala384, G384A) Thy-1 promoter |
1.5 months, before Aβ plaques deposition and cognitive impairment | Increased | Experimental paradigm: in vivo two-photon calcium imaging of the hippocampal CA1 neurons. Findings: selective increase in hyperactive neurons in hippocampus of APP23xPS45 mice before Aβ plaques deposition suggesting that soluble species of Aβ may underlie this impairment. Acute treatment with the γ-secretase inhibitor LY-411575 reduced soluble Aβ levels and rescued the neuronal dysfunction. |
| Davis et al. (2014) | 3xTg-AD (hAPP Swedish. htau P301L, and hPSEN1: M146V) Thy-1.2 promoter |
4–6 months, before Aβ plaques deposition | Increased | Experimental paradigm: in vivo hippocampal electrophysiology recordings. Findings: synaptic hyperexcitability in DG and CA1. |
| Kazim et al. (2017) | 3xTg-AD (hAPP Swedish. htau P301L, and hPSEN1: M146V) Thy-1.2 promoter |
3 weeks, before Aβ plaques deposition and cognitive impairment | Increased | Experimental paradigm: audiogenic seizure susceptibility; ex vivo hippocampal CA3 intracellular recordings after GABAA blockade with bicuculline. Findings: increased audiogenic seizure susceptibility and prolonged epileptiform discharges after bicuculline application in hippocampal CA3 intracellular recordings in 3×Tg-AD mice. |
| Fu et al. (2019) | hAPP-J20 (APP Swedish and Indiana) PDGF-β promoter |
1 and 2 months, before Aβ plaques deposition and cognitive impairment | Increased | Experimental paradigm: in vivo EEG recordings. Findings: epileptic spikes at 1 month of age with robust seizure activity at 2 months of age. |
4-AP, 4-aminopyridine; Aβ, amyloid β; DG, dentate gyrus; EC, entorhinal cortex; EEG, electroencephalogram; fEPSPs, field EPSPs; hAPP, human amyloid β precursor protein; hPSEN, human presenilin; LFPs, local field potentials; LTP. Long-term potentiation; mEPSCs, miniature EPSCs; mGluR5, metabotropic glutamate receptor 5; mIPSCs, miniature IPSCs; MPEP, 2-methyl-6-(phenylethynyl)pyridine hydrochloride; PDGF, platelet-derived growth factor; Prp, prion protein; PTZ, phenylenetetrazole; PV, parvalbumin; REM, rapid eye movement; SWDs, spike-wave discharges; WT, wild type.