TY - JOUR
T1 - Tau loss attenuates neuronal network hyperexcitability in mouse and drosophila genetic models of epilepsy
AU - Holth, Jerrah K.
AU - Bomben, Valerie C.
AU - Graham Reed, J.
AU - Inoue, Taeko
AU - Younkin, Linda
AU - Younkin, Steven G.
AU - Pautler, Robia G.
AU - Botas, Juan
AU - Noebels, Jeffrey L.
PY - 2013/1/23
Y1 - 2013/1/23
N2 - 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.
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-- (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.
UR - http://www.scopus.com/inward/record.url?scp=84872729419&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84872729419&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.3191-12.2013
DO - 10.1523/JNEUROSCI.3191-12.2013
M3 - Article
C2 - 23345237
AN - SCOPUS:84872729419
SN - 0270-6474
VL - 33
SP - 1651
EP - 1659
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 4
ER -