title: Antisense reduction of tau in adult mice protects against seizures.
abstract: 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.
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Washington University, St Louis, Missouri 63110, USA.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: DeVos
authors.forename: Dustin K
authors.initials: DK
authors.lastname: Goncharoff
authors.forename: Guo
authors.initials: G
authors.lastname: Chen
authors.forename: Carey S
authors.initials: CS
authors.lastname: Kebodeaux
authors.forename: Kaoru
authors.initials: K
authors.lastname: Yamada
authors.forename: Floy R
authors.initials: FR
authors.lastname: Stewart
authors.forename: Dorothy R
authors.initials: DR
authors.lastname: Schuler
authors.forename: Susan E
authors.initials: SE
authors.lastname: Maloney
authors.forename: David F
authors.initials: DF
authors.lastname: Wozniak
authors.forename: Frank
authors.initials: F
authors.lastname: Rigo
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.forename: John R
authors.initials: JR
authors.lastname: Cirrito
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Miller
mesh_terms: D000367:Age Factors; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D003292:Convulsants / Q000633:toxicity; D004195:Disease Models, Animal; D020233:Gait Disorders, Neurologic / Q000188:drug therapy / Q000209:etiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D057967:Infusions, Intraventricular; D019344:Lactic Acid / Q000378:metabolism; D008124:Locomotion / Q000235:genetics; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D010433:Pentylenetetrazole / Q000633:toxicity; D010852:Picrotoxin / Q000633:toxicity; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D003292:Convulsants; D019344:Lactic Acid; D016376:Oligonucleotides, Antisense; D010433:Pentylenetetrazole; D010852:Picrotoxin; D016875:tau Proteins
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