Summary of studies analyzing neuronal network excitability in tau mouse models
| Author(s) and publication year | Mouse model/transgene(s) | Age/stage of pathology | Neuronal network excitability status | Experimental paradigm/neuronal network excitability observation(s) |
|---|---|---|---|---|
| Rocher et al. (2010) | rTg4510 (htau P301L) | 8.5 months, NFTs and neurodegeneration | Increased | Experimental paradigm: in vitro whole cell patch clamp recordings of layer 3 frontal cortex pyramidal neurons. Findings: increased action potential firing rates and a significantly depolarized resting membrane potential in transgenic mice slices, independent of NFTs. |
| Hoover et al. (2010) | rTg4510 (htau P301L) Rat hippocampal neurons transfected with hτP301L | rTg4510 cultured hippocampal neurons from E18: DIV 22–30, decreased excitatory glutamate receptor levels. Rat hippocampal neurons transfected with hτP301L: DIV 22–30, increased phospho-tau | Decreased | Experimental paradigm: in vitro hippocampal neurons electrophysiology, mEPSCs recording. Findings: reduced mEPSCs frequency and amplitude both in rTg4510 cultured hippocampal neurons and rat hippocampal cultured neurons transfected with hτP301L. |
| Crimins et al. (2011) | rTg4510 (htau P301L) | 9 months, NFTs and neurodegeneration | Increased | Experimental paradigm: in vitro whole cell patch clamp recordings of layer 3 frontal cortex pyramidal neurons. Findings: increased spontaneous synaptic activity (increased frequency of sEPSCs). |
| Crimins et al. (2012) | rTg4510 (htau P301L) | < 4 (1–3) mo and > 8 (9–13) mo; soluble hyperphosphorylated tau species at <4 months, NFTs and neurodegeneration at >8 months | Increased | Experimental paradigm: in vitro whole cell patch clamp recordings of layer 3 frontal cortex pyramidal neurons. Findings: increased excitability both in early and advanced tauopathy. Depolarized resting membrane potential, an increased depolarizing sag potential and increased action potential firing rates—all indicative of hyperexcitability. Hyperexcitability reversed by suppression of human mutant tau transgene. |
| Menkes-Caspi et al. (2015) | rTg4510 (htau P301L) | 3 months, accumulation of hyperphosphorylated and misfolded tau in cortex; 5 months, pathologic tau and NFTs in cortex | Decreased | Experimental paradigm: in vivo intracellular recordings from frontal cortex in anesthetized mice, In vivo extracellular recordings/LFPs in awake behaving mice. Findings: reduced activity both of single neocortical pyramidal cells and of the neocortical network including decreased firing rates and altered firing patterns. |
| Witton et al. (2016) | rTg4510 (htau P301L) | 7–8 months, NFTs and neurodegeneration | Increased | Experimental paradigm: in vivo hippocampal CA1 electrophysiology recordings, both single-unit and LFPs. Findings: increased propensity of excitatory pyramidal neurons in hippocampus to fire action potentials in a phase locked manner during SWRs; inhibitory interneurons were less likely to fire phase‐locked spikes during SWRs. |
| Hatch et al. (2017) | rTg4510 (htau P301L, 13-fold higher human tau expression as compared with endogenous tau) pR5 (htau P301L, at lower level than rTg4510, 0.7-fold higher human tau as compared with endogenous tau) | rTg4510: 1–2 months, early stage tauopathy before overt tau hyperphosphorylation and synaptic impairment 4–6 months, mid-stage with extensive tau hyperphosphorylation and impairment of synaptic activity and spatial memory 12–14 months, late stage with synaptic loss and neurodegeneration PR5: 15–17 months, tau pathology in hippocampus | Decreased | Experimental paradigm: in vitro whole cell patch clamp recordings from hippocampal CA1 pyramidal neurons. Findings: reduced action potential firing rate because of a depolarization shift in action potential generation and reduced action potential amplitude at all ages in the CA1 pyramidal neurons of P301L mice. pR5 mice CA1 pyramidal neurons showed less severe action potential impairment compared with rTg4510, including action potential depolarization shift and reduced action potential amplitude. |
| Busche et al. (2019) | rTg4510 (htau P301L) rTg21221 (htau overexpression) | rTg4510: 6–12 months, tau aggregation and NFTs 3–4 months; soluble tau. rTg21221: 6–12 months, human tau overexpression. | Decreased | Experimental paradigm: in vivo two-photon Ca2+ imaging of neurons in layer 2/3 of the cortex. Findings: strong reduction in cortical activity as reflected by increased number of silent neurons in both 6- to 12- and 3- to 4-month-old rTg4510 mice. Reduction in cortical activity in 6- to 12-month-old rTg2210 mice. Reducing tau in 3- to 4-month-old rTg4510 mice decreased the number of silent neurons. |
| Van Erum et al. (2020) | tau58/4 (htau P301S) | 3 months, htau and phospho-tau in the frontal cortex and pons 12–15 months, NFTs throughout the brain. | Increased | Experimental paradigm: video EEG recordings; PTZ-induced seizure susceptibility. Findings: increased PTZ-induced seizure susceptibility in young (3-month-old) tau58/4 mice as compared with age-matched WT littermates. Young tau58/4 animals displayed more severe seizures and had a reduced latency to the first seizure compared with WTs. While, age-related differences in susceptibility could be demonstrated for both genotypes, old tau58/4 did not exhibit a significantly higher seizure susceptibility as compared with WT mice. |
| Marinković et al. (2019) | P301S (htau P301S) | 2 m, injected with tau preformed fibrils for NFTs seeding, evaluated for cortical activity up to 50 d after injections | Decreased | Experimental paradigm: in vivo two-photon Ca2+ imaging of neurons in layer 2/3 of the cortex in awake, head-fixed mice. Findings: strong reduction in cortical activity, independent of NFTs presence, suggesting the impairing role of soluble, mutated tau protein species. |
| Mondragón-Rodríguez et al. (2018b) | 3xTg-AD (htau P301L, hAPP Swedish, hPSEN1) | 1 month, increased phospho-tau, intraneuronal APP/Aβ, prior to cognitive impairment. | Decreased | Experimental paradigm: in vitro whole cell patch clamp recordings from hippocampal CA1 pyramidal neurons; in vitro LFPs recordings from hippocampal slices. Findings: no difference in amplitude and frequency of action potentials between 3×Tg-AD and non-Tg CA1 pyramidal neurons. Overall, the young 3×Tg-AD mice showed less excitable hippocampal network activity, likely related to abnormally hyperphosphorylated tau at microtubule domain region (MDr). |
| Ahnaou et al. (2017) | Tg tau P301L (h tau P301L) | 3 months, injected with preformed tau fibrils to induce tau aggregation. | Normal | Experimental paradigm: in vivo EEG recordings. Network oscillations, phase amplitude cross frequency coupling, mismatch negativity (MMN) of event related brain potentials, and coherence was analyzed. Findings: weakening of θ oscillations, drastic impairments in θ–γ oscillations phase-amplitude cross frequency coupling, and disrupted MMN complex amplitude (all vital for memory and learning performance) induced by tau seeding. No epileptiform activity or network hyperexcitability. |
| Angulo et al. (2017) | EC-htau (hτP301L) EC-hAPP (hAPP) EC-hAPP/htau (hAPP, hτP301L) | EC-htau: 2.5–3.5 months, htau and phospho-tau accumulation in EC. EC-hAPP: 2.5–3.5 months, soluble Aβ. | Normal/ resistance to induced-hyperexcitability in EC-htau mice | Experimental paradigm: in vitro hippocampal EC/subiculum electrophysiology recordings: single electrode evoked and sEFPs, single neuron patch clamp, and extracellular multielectrode recordings. Findings: mutated htau induced resistance to EC-hippocampus hyperexcitability in EC-htau mice evidenced by resistance to increased network activity evaluated by sEFP durations after GABAA blockade with picrotoxin. Increased neuronal excitability in EC in EC-hAPP mice evidenced by higher frequency of relatively prolonged sEFPs in lateral EC and epileptiform-ictal like discharges in medial EC. While no differences were observed in sEFPs duration and frequency in EC/CA1/subiculum regions (using multielectrode recordings) between EC-hAPP/htau mice and WT mice, a smaller percentage of slices displayed epileptiform discharges. Co-expression of hAPP and htau produced an intermediate phenotype, mostly driven by tau |
| Maeda et al. (2016) | htau-A152T | 4–9 months, soluble tau | Increased | Experimental paradigm: in vivo EEG recordings in awake behaving mice; epileptic spikes quantification both at baseline and after injection of non-convulsive dose of PTZ. Findings: increased epileptic spike counts both at baseline and after PTZ injection in htau-A152T mice as compared with non-Tg controls. |
| Decker et al. (2016) | htau-A152T | 12–14 months, accumulation of hyperphosphorylated and missorted tau, neurodegeneration, and synaptic loss in hippocampal CA3 region. Increased phospho-tau in hippocampal slice cultures at DIV 10. | Increased | Experimental paradigm: in vivo EEG recordings in awake behaving mice; epileptic spikes quantification both at baseline and after injection of non-convulsive dose of PTZ. Findings: enhanced basal synaptic transmission in CA3 region of the hippocampus in htau-A152T mice (increased fEPSPs in mossy fiber pathway in acute slices from 12-month-old mice and increased somatic field potentials in stratum pyramidale of area CA3 in organotypic hippocampal slices at DIV 30. Increase in picrotoxin-induced epileptiform burst frequency as well as in firings per burst in organotypic slice cultures expression htau-A152T mutation (both at DIV 10 and 30) which was prevented by ceftriaxone (stimulates astrocytic glutamate uptake via the transporter EAAT2/GLT1). |
| Das et al. (2018) | htau-A152T | 4–6 months; soluble tau | Increased | Experimental paradigm: in vivo EEG recordings; epileptic spikes quantification. Findings: increased epileptic spike counts at resting state in htau-A152T mice as compared with non-Tg controls. Antiepileptic drug levetiracetam treatment reduced epileptic spike counts in htau-A152T mice. |
| García-Cabrero et al. (2013) | FTDP-17 mice (htau G272V, P301L, and R406W; Overexpression of human tau isoform with 2 N-terminal inserts, 4-microtubule-binding-repeat elements) | 1–5, 6–14, and 15–22 months; mutant tau transgene overexpressed at 3 m of age, activated microglia at 4 months, reactive astrocytes at 9 months, and phospho-tau aggregates at 18–20 months | Increased | Experimental paradigm: in vivo video EEG recordings and PTZ-seizure susceptibility testing. Findings: spontaneous epileptiform activity and epileptic seizures in 70% of FTDP-17 mice at the age of 5.5 m and thereafter. Increased PTZ-induced seizures susceptibility at 6–14 months of age and thereafter. |
Aβ, amyloid β; EC, entorhinal cortex; DIV, days in vitro; EAAT2, excitatory amino acid transporter 2; EEG, electroencephalogram; fEPSPs, field EPSPs; FTDP, frontotemporal dementia with parkinsonism; GLT1, glutamate transporter 1; hAPP, human amyloid β precursor protein; hPSEN, human presenilin; LFPs, local field potentials; mEPSCs, miniature EPSCs; NFTs, neurofibrillary tangles; PTZ, phenylenetetrazole; sEFPs, spontaneous extracellular field potentials; sEPSCs, spontaneous EPSCs; SWDs, spike-wave discharges; SWRs, sharp-wave ripples; Tg, transgenic; WT, wild type.