Both p35/CDK5 and calpain-1 (via proteinase activity288) closely regulate the turnover of NMDAR subunit NR2B on the membrane surface, and affect hippocampal spatial learning and LTP.289,290 Therefore, enhanced TTBK1 activity is assumed to upregulate p35/CDK5 and calpain-1 activity, which causes cognitive impairment via endocytosis and degradation of NMDAR. The gene discussed is CDK5R1; the disease is Cognitive impairment.