Tau loss attenuates neuronal network hyperexcitability in mouse and Drosophila genetic models of epilepsy.
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.
Developmental Neurogenetics Laboratory, Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.
Jerrah K
JK
Holth
Valerie C
VC
Bomben
J Graham
JG
Reed
Taeko
T
Inoue
Linda
L
Younkin
Steven G
SG
Younkin
Robia G
RG
Pautler
Juan
J
Botas
Jeffrey L
JL
Noebels
D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004330:Drosophila; D004569:Electroencephalography; D004797:Enzyme-Linked Immunosorbent Assay; D004827:Epilepsy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009415:Nerve Net / Q000378:metabolism / Q000503:physiopathology*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D016875:tau Proteins / Q000378:metabolism*
D016875:tau Proteins