Calpain Cleaves a Memory Inhibitor

Abstract

Calpain, a calcium-dependent protease, has been implicated in neuronal responses to various stimuli, and Shimizu et al . provide evidence that calpain contributes to certain types of learning and memory. Shimizu et al . (see commentary by Bolshakov) found that suprachiasmatic nucleus circadian oscillatory protein (SCOP) was abundant in the hippocampus of mice and rats. Overexpression of SCOP in cultured hippocampal neurons decreased the expression of an adenosine 3′,5′-monophosphate (cAMP) response element (CRE)-regulated reporter gene stimulated by brain-derived neurotrophic factor (BDNF), whereas knockdown of the endogenous protein using RNA interference enhanced reporter gene expression in the presence or absence of BDNF. CRE-mediated gene expression is downstream of activation of mitogen-activated protein kinases (MAPKs) and contributes to synaptic changes involved in learning and memory. SCOP was previously reported to inhibit K-Ras by sequestering the nucleotide-free form, thereby inhibiting MAPK activation. The authors found that SCOP abundance was decreased in cultured hippocampal neurons stimulated with BDNF, the glutamate receptor agonist NMDA, or KCl. Assays for SCOP cleavage in cell-free extracts in the presence of various protease pharmacological inhibitors indicated that calpains, not caspase 3 or the proteasome, cleaved SCOP and that SCOP cleavage required calcium. In cultured hippocampal neurons, calpain inhibition blocked SCOP degradation and decreased the phosphorylation (and activation) of the MAPK ERK-2 stimulated by BDNF. In mice, memory for new objects was associated with a decrease in the abundance of SCOP (in whole hippocampal extracts). Mice overexpressing SCOP using an inducible promoter showed decreased memory for new objects 24 hours after object training but no deficiency in short-term memory. Consistent with a role for calpain in memory, administration of a calpain inhibitor into the hippocampus blocked new object memory after 24 hours but had no effect on short-term memory measured after 8 minutes. K. Shimizu, T. Phan, I. M. Mansuy, D. R. Storm, Proteolytic degradation of SCOP in the hippocampus contributes to activation of MAP kinase and memory. Cell 128 , 1219-1229 (2007). [Online Journal] V. Y. Bolshakov, SCOPing out proteases in long-term memory. Cell 128 , 1029-1030 (2007). [Online Journal]