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 ofMapt, the gene encoding tau, in AD models overexpressing amyloid-β (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 andDrosophilamodels of hyperexcitability.Kcna1^−/−mice lack Kv1.1-delayed rectifier currents and exhibit severe spontaneous seizures, early lethality, and megencephaly. YoungKcna1^−/−mice retained wild-type levels of Aβ, tau, and tau phospho-Thr²³¹. Decreasing tau inKcna1^−/−mice reduced hyperexcitability and alleviated seizure-related comorbidities. Tau reduction decreasedKcna1^−/−video-EEG recorded seizure frequency and duration as well as normalizedKcna1^−/−hippocampal network hyperexcitabilityin vitro. Additionally, tau reduction increasedKcna1^−/−survival and prevented megencephaly and hippocampal hypertrophy, as determined by MRI. Bang-sensitiveDrosophilamutants 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,kccandeas. 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.