title: Tau reduction diminishes spatial learning and memory deficits after mild repetitive traumatic brain injury in mice.
abstract: OBJECTIVE
  Because reduction of the microtubule-associated protein Tau has beneficial effects in mouse models of Alzheimer's disease and epilepsy, we wanted to determine whether this strategy can also improve the outcome of mild traumatic brain injury (TBI).
  
  
  METHODS
  We adapted a mild frontal impact model of TBI for wildtype C57Bl/6J mice and characterized the behavioral deficits it causes in these animals. The Barnes maze, Y maze, contextual and cued fear conditioning, elevated plus maze, open field, balance beam, and forced swim test were used to assess different behavioral functions. Magnetic resonance imaging (MRI, 7 Tesla) and histological analysis of brain sections were used to look for neuropathological alterations. We also compared the functional effects of this TBI model and of controlled cortical impact in mice with two, one or no Tau alleles.
  
  
  RESULTS
  Repeated (2-hit), but not single (1-hit), mild frontal impact impaired spatial learning and memory in wildtype mice as determined by testing of mice in the Barnes maze one month after the injury. Locomotor activity, anxiety, depression and fear related behaviors did not differ between injured and sham-injured mice. MRI imaging did not reveal focal injury or mass lesions shortly after the injury. Complete ablation or partial reduction of tau prevented deficits in spatial learning and memory after repeated mild frontal impact. Complete tau ablation also showed a trend towards protection after a single controlled cortical impact. Complete or partial reduction of tau also reduced the level of axonopathy in the corpus callosum after repeated mild frontal impact.
  
  
  CONCLUSIONS
  Tau promotes or enables the development of learning and memory deficits and of axonopathy after mild TBI, and tau reduction counteracts these adverse effects.
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, United States of America; Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Cheng
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, United States of America.
authors.forename: Ryan
authors.initials: R
authors.lastname: Craft
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, United States of America.
authors.forename: Gui-Qiu
authors.initials: GQ
authors.lastname: Yu
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, United States of America.
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Ho
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, United States of America.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Geetha
authors.initials: G
authors.lastname: Mohan
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Sergey
authors.initials: S
authors.lastname: Mangnitsky
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, United States of America.
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Ponnusamy
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, United States of America; Department of Neurology, University of California San Francisco, California, United States of America.
authors.forename: Lennart
authors.initials: L
authors.lastname: Mucke
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology; D001930:Brain Injuries / Q000503:physiopathology*; D003337:Corpus Callosum / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D008279:Magnetic Resonance Imaging; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory; D008569:Memory Disorders / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065853:Spatial Learning / Q000502:physiology*; D016875:tau Proteins / Q000235:genetics*
chemical_list: C558298:Mapt protein, mouse; D016875:tau Proteins