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

88 Citations (Scopus)

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

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Genetic Models
Drosophila
Epilepsy
Seizures
Nervous System Diseases
Alzheimer Disease
Microtubule Proteins
Amyloid
Paralysis
Hypertrophy
Comorbidity
Electroencephalography
Carrier Proteins
Genes

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Tau loss attenuates neuronal network hyperexcitability in mouse and drosophila genetic models of epilepsy. / Holth, Jerrah K.; Bomben, Valerie C.; Graham Reed, J.; Inoue, Taeko; Younkin, Linda; Younkin, Steven G; Pautler, Robia G.; Botas, Juan; Noebels, Jeffrey L.

In: Journal of Neuroscience, Vol. 33, No. 4, 23.01.2013, p. 1651-1659.

Research output: Contribution to journalArticle

Holth, JK, Bomben, VC, Graham Reed, J, Inoue, T, Younkin, L, Younkin, SG, Pautler, RG, Botas, J & Noebels, JL 2013, 'Tau loss attenuates neuronal network hyperexcitability in mouse and drosophila genetic models of epilepsy', Journal of Neuroscience, vol. 33, no. 4, pp. 1651-1659. https://doi.org/10.1523/JNEUROSCI.3191-12.2013
Holth, Jerrah K. ; Bomben, Valerie C. ; Graham Reed, J. ; Inoue, Taeko ; Younkin, Linda ; Younkin, Steven G ; Pautler, Robia G. ; Botas, Juan ; Noebels, Jeffrey L. / Tau loss attenuates neuronal network hyperexcitability in mouse and drosophila genetic models of epilepsy. In: Journal of Neuroscience. 2013 ; Vol. 33, No. 4. pp. 1651-1659.
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AU - Pautler, Robia G.

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AU - Noebels, Jeffrey L.

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