Calpastatin overexpression limits calpain-mediated proteolysis and behavioral deficits following traumatic brain injury

► hCAST overexpression in transgenic mice effectively reduced protease activity. ► Brain injury-induced spectrin proteolysis was blunted in hCAST transgenic mice. ► hCAST overexpression partially protected the hippocampus but not cortex after TBI. ► Motor function was improved in brain-injured mice overexpressing hCAST. ► In mice with TBI, object recognition memory was improved by hCAST overexpression.