title: Tau reduction prevents disease in a mouse model of Dravet syndrome.
abstract: OBJECTIVE
  Reducing levels of the microtubule-associated protein tau has shown promise as a potential treatment strategy for diseases with secondary epileptic features such as Alzheimer disease. We wanted to determine whether tau reduction may also be of benefit in intractable genetic epilepsies.
  
  
  METHODS
  We studied a mouse model of Dravet syndrome, a severe childhood epilepsy caused by mutations in the human SCN1A gene encoding the voltage-gated sodium channel subunit Nav 1.1. We genetically deleted 1 or 2 Tau alleles in mice carrying an Nav 1.1 truncation mutation (R1407X) that causes Dravet syndrome in humans, and examined their survival, epileptic activity, related hippocampal alterations, and behavioral abnormalities using observation, electroencephalographic recordings, acute slice electrophysiology, immunohistochemistry, and behavioral assays.
  
  
  RESULTS
  Tau ablation prevented the high mortality of Dravet mice and reduced the frequency of spontaneous and febrile seizures. It reduced interictal epileptic spikes in vivo and drug-induced epileptic activity in brain slices ex vivo. Tau ablation also prevented biochemical changes in the hippocampus indicative of epileptic activity and ameliorated abnormalities in learning and memory, nest building, and open field behaviors in Dravet mice. Deletion of only 1 Tau allele was sufficient to suppress epileptic activity and improve survival and nesting performance.
  
  
  CONCLUSIONS
  Tau reduction may be of therapeutic benefit in Dravet syndrome and other intractable genetic epilepsies.
authors.affiliation: Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA; Departments of Pathology, University of California, San Francisco, San Francisco, CA.
authors.forename: Ania L
authors.initials: AL
authors.lastname: Gheyara
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Ponnusamy
authors.forename: Biljana
authors.initials: B
authors.lastname: Djukic
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Craft
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Ho
authors.forename: Weikun
authors.initials: W
authors.lastname: Guo
authors.forename: Mariel M
authors.initials: MM
authors.lastname: Finucane
authors.forename: Pascal E
authors.initials: PE
authors.lastname: Sanchez
authors.forename: Lennart
authors.initials: L
authors.lastname: Mucke
mesh_terms: D000483:Alleles; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D004195:Disease Models, Animal; D004569:Electroencephalography; D004831:Epilepsies, Myoclonic / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D005260:Female; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007858:Learning / Q000502:physiology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics; D012640:Seizures / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; C568249:Scn1a protein, mouse; D016875:tau Proteins