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

J Neurosci. 2013 Jan 23;33(4):1651-9. doi: 10.1523/JNEUROSCI.3191-12.2013.

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-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-Thr(231). 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Disease Models, Animal
  • Drosophila
  • Electroencephalography
  • Enzyme-Linked Immunosorbent Assay
  • Epilepsy / genetics
  • Epilepsy / metabolism*
  • Epilepsy / physiopathology*
  • Female
  • Hippocampus / metabolism
  • Hippocampus / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Net / metabolism
  • Nerve Net / physiopathology*
  • Organ Culture Techniques
  • Patch-Clamp Techniques
  • tau Proteins / metabolism*

Substances

  • tau Proteins