Tau Loss Attenuates Neuronal Network Hyperexcitability in Mouse andDrosophilaGenetic Models of Epilepsy

Abstract

Neuronal network hyperexcitability underlies the pathogenesis of seizures and is a component of some degenerative neurological disorders such as Alzheimer’s disease (AD). Recently, the microtubule binding protein tau has been implicated in the regulation of network synchronization. Genetic removal of Mapt, the gene encoding tau, in AD models overexpressing amyloid-beta (Aβ) decreases hyperexcitability and normalizes the excitation/inhibition imbalance. Whether this effect of tau removal is specific to Aβ mouse models remains to be determined. Here we examined tau as an excitability modifier in the non-AD nervous system using genetic deletion of tau in mouse and Drosophila models of hyperexcitability. Kcna1−/− mice lack Kv1.1 delayed rectifier currents and exhibit severe spontaneous seizures, early lethality, and megencephaly. Young Kcna1−/− mice retained wild-type levels of Aβ, tau, and tau phospho-Thr231. Decreasing tau in Kcna1−/− mice reduced hyperexcitability and alleviated seizure-related comorbidities. Tau reduction decreased Kcna1−/− video-EEG recorded seizure frequency and duration as well as normalized Kcna1−/− hippocampal network hyperexcitability in vitro. Additionally, tau reduction increased Kcna1−/− survival and prevented megencephaly and hippocampal hypertrophy, as determined by MRI. Bang-sensitive Drosophila mutants display paralysis and seizures in response to mechanical stimulation, providing a complementary excitability assay for epistatic interactions. We found that tau reduction significantly decreased seizure sensitivity in two independent bang-sensitive mutant models, kcc and eas. Our results indicate that tau plays a general role in regulating intrinsic neuronal network hyperexcitability independently of Aβ overexpression and suggest that reducing tau function could be a viable target for therapeutic intervention in seizure disorders and antiepileptogenesis.

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

“…Possibly related to this effect—and consistent with the observation that reduction of endogenous tau blocks network hyperexcitability and epilepsy of diverse causes 50, 67, 83, 84, 85—both hTau‐WT mice and hTau‐A152T mice were more susceptible to chemically induced epileptiform activity. Similar findings were obtained in hippocampal slice cultures from an independent hTau‐A152T mouse model 74 and in hTau mice carrying the FTDP‐17 mutations G272V, P301L, and R406W 86.…”

Network dysfunction in α‐synuclein transgenic mice and human Lewy body dementia

“…6B and C). Similarly, ablation of the microtubule‐associated protein tau, which has been shown to reduce epileptic activity in a variety of seizure models,28, 30, 31, 32, 33, 34 tended to reduce interictal events by roughly 50% but, if anything, tended to slightly increase the left shift in spectral power in SYN mice (Fig. 6D and E).…”

Novel function of Tau in regulating the effects of external stimuli on adult hippocampal neurogenesis

“…Tau absence confers neuroprotection in several models of neuronal damage, such as traumatic brain injury (Cheng et al , 2014), neuroinflammation (Maphis et al , 2015), amyloid β‐mediated excitotoxicity (Roberson et al , 2007, 2011; Ittner et al , 2010; Vossel et al , 2010), and epilepsy (Holth et al , 2013), among others. Given that acute stress negatively affects AHN (Gould et al , 1992) and considering the neuroprotection exerted by the lack of Tau in the aforementioned models, we addressed whether the Porsolt test would cause similar detrimental effects in Tau −/− and WT mice.…”