PT - JOURNAL ARTICLE AU - Jerrah K. Holth AU - Valerie C. Bomben AU - J. Graham Reed AU - Taeko Inoue AU - Linda Younkin AU - Steven G. Younkin AU - Robia G. Pautler AU - Juan Botas AU - Jeffrey L. Noebels TI - Tau Loss Attenuates Neuronal Network Hyperexcitability in Mouse and <em>Drosophila</em> Genetic Models of Epilepsy AID - 10.1523/JNEUROSCI.3191-12.2013 DP - 2013 Jan 23 TA - The Journal of Neuroscience PG - 1651--1659 VI - 33 IP - 4 4099 - http://www.jneurosci.org/content/33/4/1651.short 4100 - http://www.jneurosci.org/content/33/4/1651.full SO - J. Neurosci.2013 Jan 23; 33 AB - 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-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 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.