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PLoS One. 2014 Dec 31;9(12):e115765. doi: 10.1371/journal.pone.0115765. eCollection 2014.

Tau reduction diminishes spatial learning and memory deficits after mild repetitive traumatic brain injury in mice.

Author information

1
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.
2
Gladstone Institute of Neurological Disease, San Francisco, California, United States of America.
3
Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California, United States of America.
4
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.

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.

INTERPRETATION:

Tau promotes or enables the development of learning and memory deficits and of axonopathy after mild TBI, and tau reduction counteracts these adverse effects.

PMID:
25551452
PMCID:
PMC4281043
DOI:
10.1371/journal.pone.0115765
[Indexed for MEDLINE]
Free PMC Article

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