PT  - JOURNAL ARTICLE
AU  - Sarah L. DeVos
AU  - Dustin K. Goncharoff
AU  - Guo Chen
AU  - Carey S. Kebodeaux
AU  - Kaoru Yamada
AU  - Floy R. Stewart
AU  - Dorothy R. Schuler
AU  - Susan E. Maloney
AU  - David F. Wozniak
AU  - Frank Rigo
AU  - C. Frank Bennett
AU  - John R. Cirrito
AU  - David M. Holtzman
AU  - Timothy M. Miller
TI  - Antisense Reduction of Tau in Adult Mice Protects against Seizures
AID  - 10.1523/JNEUROSCI.2107-13.2013
DP  - 2013 Jul 31
TA  - The Journal of Neuroscience
PG  - 12887--12897
VI  - 33
IP  - 31
4099  - http://www.jneurosci.org/content/33/31/12887.short
4100  - http://www.jneurosci.org/content/33/31/12887.full
SO  - J. Neurosci.2013 Jul 31; 33
AB  - Tau, a microtubule-associated protein, is implicated in the pathogenesis of Alzheimer's Disease (AD) in regard to both neurofibrillary tangle formation and neuronal network hyperexcitability. The genetic ablation of tau substantially reduces hyperexcitability in AD mouse lines, induced seizure models, and genetic in vivo models of epilepsy. These data demonstrate that tau is an important regulator of network excitability. However, developmental compensation in the genetic tau knock-out line may account for the protective effect against seizures. To test the efficacy of a tau reducing therapy for disorders with a detrimental hyperexcitability profile in adult animals, we identified antisense oligonucleotides that selectively decrease endogenous tau expression throughout the entire mouse CNS—brain and spinal cord tissue, interstitial fluid, and CSF—while having no effect on baseline motor or cognitive behavior. In two chemically induced seizure models, mice with reduced tau protein had less severe seizures than control mice. Total tau protein levels and seizure severity were highly correlated, such that those mice with the most severe seizures also had the highest levels of tau. Our results demonstrate that endogenous tau is integral for regulating neuronal hyperexcitability in adult animals and suggest that an antisense oligonucleotide reduction of tau could benefit those with epilepsy and perhaps other disorders associated with tau-mediated neuronal hyperexcitability.