Tau loss attenuates neuronal network hyperexcitability in mouse and drosophila genetic models of epilepsy

Jerrah K. Holth, Valerie C. Bomben, J. Graham Reed, Taeko Inoue, Linda Younkin, Steven G. Younkin, Robia G. Pautler, Juan Botas, Jeffrey L. Noebels

Research output: Contribution to journalArticle

108 Scopus citations

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-- (A-) decreases hyperexcitability and normalizes the excitation/inhibition imbalance. Whether this effect of tau removal is specific to A- 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 ofA-, 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.

Original languageEnglish (US)
Pages (from-to)1651-1659
Number of pages9
JournalJournal of Neuroscience
Volume33
Issue number4
DOIs
StatePublished - Jan 23 2013

ASJC Scopus subject areas

  • Neuroscience(all)

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    Holth, J. K., Bomben, V. C., Graham Reed, J., Inoue, T., Younkin, L., Younkin, S. G., Pautler, R. G., Botas, J., & Noebels, J. L. (2013). Tau loss attenuates neuronal network hyperexcitability in mouse and drosophila genetic models of epilepsy. Journal of Neuroscience, 33(4), 1651-1659. https://doi.org/10.1523/JNEUROSCI.3191-12.2013