title: Relationship of calpain-mediated proteolysis to the expression of axonal and synaptic plasticity markers following traumatic brain injury in mice.
abstract: The role of neuronal plasticity and repair on the final functional outcome following traumatic brain injury (TBI) remains poorly understood. Moreover, the relationship of the magnitude of post-traumatic secondary injury and neurodegeneration to the potential for neuronal repair has not been explored. To address these questions, we employed Western immunoblotting techniques to examine how injury severity affects the spatial and temporal expression of markers of axonal growth (growth-associated protein GAP-43) and synaptogenesis (pre-synaptic vesicular protein synaptophysin) following either moderate (0.5 mm, 3.5 M/s) or severe (1.0 mm, 3.5 M/s) lateral controlled cortical impact traumatic brain injury (CCI-TBI) in young adult male CF-1 mice. Moderate CCI increased GAP-43 levels at 24 and 48 h post-insult in the ipsilateral hippocampus relative to sham, non-injured animals. This increase in axonal plasticity occurred prior to maximal hippocampal neurodegeneration, as revealed by de Olmos silver staining, at 72 h. However, moderate CCI-TBI did not elevate GAP-43 expression in the ipsilateral cortex where neurodegeneration was extensive by 6 h post-TBI. In contrast to moderate injury, severe CCI-TBI failed to increase hippocampal GAP-43 levels and instead resulted in depressed GAP-43 expression in the ipsilateral hippocampus and cortex at 48 h post-insult. In regards to injury-induced changes in synaptogenesis, we found that moderate CCI-TBI elevated synaptophysin levels in the ipsilateral hippocampus at 24, 48, 72 h and 21 days, but this effect was not present after severe injury. Together, these data highlights the adult brain's ability for axonal and synaptic plasticity following a focal cortical injury, but that severe injuries may diminish these endogenous repair mechanisms. The differential effects of moderate versus severe TBI on the post-traumatic plasticity response may be related to the calpain-mediated proteolytic activity occurring after a severe injury preventing increased expression of proteins required for plasticity. Supporting this hypothesis is the fact that GAP-43 is a substrate for calpain along with our data demonstrating that calpain-mediated degradation of the cytoskeletal protein, alpha-spectrin, is approximately 10 times greater in ipsilateral hippocampal tissue following severe compared to moderate CCI-TBI. Thus, TBI severity has a differential effect on the injury-induced neurorestorative response with calpain activation being one putative factor contributing to neuroregenerative failure following severe CCI-TBI. If true, then calpain inhibition may lead to both neuroprotective effects and an enhancement of neuronal plasticity/repair mechanisms post-TBI.
authors.affiliation: Spinal Cord and Brain Injury Research Center, University of Kentucky Chandler Medical Center, Lexington, Kentucky, USA.
authors.forename: Stephanie N
authors.initials: SN
authors.lastname: Thompson
authors.forename: Tonya R
authors.initials: TR
authors.lastname: Gibson
authors.forename: Brian M
authors.initials: BM
authors.lastname: Thompson
authors.forename: Ying
authors.initials: Y
authors.lastname: Deng
authors.forename: Edward D
authors.initials: ED
authors.lastname: Hall
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D001930:Brain Injuries / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D002154:Calpain / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D019922:GAP-43 Protein / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D009410:Nerve Degeneration / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology; D013049:Spectrin / Q000378:metabolism; D013569:Synapses / Q000502:physiology; D016708:Synaptophysin / Q000378:metabolism; D013997:Time Factors
chemical_list: D015415:Biomarkers; D019922:GAP-43 Protein; D009419:Nerve Tissue Proteins; D016708:Synaptophysin; D013049:Spectrin; D002154:Calpain