Postnatal calpain inhibition elicits cerebellar cell death and motor dysfunction.

Calpain-1 deletion elicits neurodevelopmental disorders, such as ataxia. However, the function of calpain in postnatal neurodevelopment and its mechanisms remain unknown. In this study, we revealed that postnatal intraperitoneal injection of various calpain inhibitors attenuated cerebellar cytosolic calpain activity. Moreover, postnatal application of calpeptin (2 mg/kg) apparently reduced spectrin breakdown, promoted suprachiasmatic nucleus circadian oscillatory protein (SCOP) accumulation in cerebellar tissue. In addition, application of calpeptin decreased phosphorylated protein kinase B (p-AKT) level (p<0.05), as well as total AKT level (p<0.05). We also evidenced that administration of calpeptin obviously increased phosphorylation of mammalian target of rapamycin (p-mTor) (p<0.01). Apoptosis of granular cells and activation of caspase-3 (p<0.01) were facilitated after calpain inhibition. Importantly, cell numbers of granular cells were reduced and motor function was remarkably impaired in 4-month-old rats receiving postnatal calpain inhibition. Taken together, our data implicated that calpain activity in the postnatal period was critical for the cerebellar development. Postnatal calpain inhibition causes cerebellar granular cell apoptosis and motor dysfunction, likely through SCOP/AKT and p-mTor signaling pathways.