Ubiquitous calpastatin overexpression in brain-injured mice attenuates motor and cognitive behavioral deficits without overt neuroprotection.

Abstract

Calpains are a family of calcium-dependent cysteine proteases that are activated within the brain minutes after a traumatic brain injury (TBI). Sustained calpain activation contributes to the secondary injury cascade of TBI and has been linked to neuronal and axonal degeneration and impairment of neurological function. Calpastatin is an endogenous protein encoded by the CAST gene which serves as a potent and highly selective inhibitor of calpains. This study investigates the potential of overexpressing human calpastatin (hCAST) via the ubiquitous prion protein promoter in a mouse model to alleviate TBI-induced brain damage and neurobehavioral dysfunction. Transgenic mice overexpressing hCAST and wildtype controls received a controlled cortical impact to induce contusive TBI or a sham injury. Overexpression of calpastatin significantly attenuated motor deficits over the first week in brain-injured mice. Visuospatial learning ability assessed in a Morris water maze on days 6 through 9 and novel object recognition on day 10 were impaired following TBI in wildtype mice. Both learning and memory function were improved in brain-injured hCAST overexpressing mice compared to wildtype mice. At 10 days post-injury brains were evaluated for cortical tissue damage and hippocampal neuron death. Analysis of Nissl-stained brain sections revealed no significant difference in the size of the cortical contusion between hCAST and wildtype animals. Similarly, hippocampal neurodegeneration associated with TBI was not modulated by hCAST overexpression. These findings demonstrate that inhibition of calpains aids in restoration of neurobehavioral function following TBI without protecting against cortical or hippocampal neuron death.