Ca²⁺/ calmodulin-dependent protein kinases (CaMKs) are widely distributed in neuron and glial cells such as astrocyte or microglia of the mammalian brain and play a critical role in cortical functions including cognition, attention, and memory.CaMKs family is mainly comprised of calcium/calmodulin-dependent protein kinase I, Ca²⁺/ calmodulin-dependent protein kinase II（CaMKII）, and Ca²⁺/ calmodulin-dependent protein kinase IV (CaMKIV). CaMKII is predominantlyexpressed in the dendritic spine of excitatory pyramidal neurons and CaMKIV is predominantly localized in the nucleus of neurons. We previously reported that downregulation of CaMKII and CaMKIV activities is critical for cognitive decline and depressive-like behaviors in pathological animal model. Especially, inhibition of ATP-sensitive K⁺ (K_ATP) channels increased intracellular Ca²⁺ concentration and CaMKII autophosphorylation and improved cognitive decline in AD model mice. By contrast, CaMKIV null mouse reveals increased hippocampal adult neurogenesis which is correlated with drug-resistant depression. In this symposium, we focus the age-related cognitive/mental disorders via calcium signal pathways.