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Head trauma induces calpain hyperactivation in neurons and glial cells.Calpain activation results in spectrin and GFAP breakdown products (BDPs).SNJ-1945 inhibits calpain following neurotrauma and reduces the levels of BDPs.PrPC is resistant to calpain and not affected by CHI-induced calpain activation.CHI is not affected by, nor does it have an influence on, PrPC expression.The normal cellular prion protein (PrPC) is a sialoglycoprotein with a glycophosphatidylinositol anchor and expressed in highest levels within the CNS particularly at neuronal synapses. This membrane-bound protein is involved with many cell functions including cell signaling and neuroprotection.Calpains are calcium-activated cysteine proteases that typically undergo controlled activation. PrPC is a calpain substrate and is neurotoxic if it undergoes aberrant processing with cytosol accumulation. Following traumatic brain injury (TBI), there is an abnormal influx of Ca+2 and overactivation of calpains resulting in neuronal dysfunction and cell death. We investigated whether PrPC expression and calpain activity have an effect on, or are affected by, TBI.PrPC expression in the hippocampus, cortex and cerebellum of WT and Tga20 (PrPC overexpression) mice were unchanged after closed head injury (CHI). Further, PrPC in WT and Tga20 mice was resistant to TBI-induced calpain proteolysis.CHI-induced calpain activation resulted in breakdown products (BDPs) of αII-spectrin (SBDPs) and GFAP (GBDP-44 K) in all brain regions and mouse lines. CHI caused significant increases in SBDP145, GFAP and GBDP-44 K when compared to sham. With few exceptions, the calpain inhibitor, SNJ-1945, reduced SBDP145 and GBDP-44 K levels. Behavioral studies suggested that PrPC and calpain independently affect learning and memory. Overall, we conclude that: (i) there is SNJ-1945-sensitive calpain activation in both neuron and glial cells following CHI, (ii) closed head trauma is not affected by, nor does it have an influence on, PrPC expression, and (iii) PrPC expression plays a minor role, if any, in CHI-induced calpain activation in vivo.