Regulation of CaMKII by α4/PP2Ac contributes to learning and memory

Ca²⁺-dependent CaMKIIα activation with autophosphorylation plays an essential role in learning and memory. The regulation of CaMKIIα by dephosphorylation by protein phosphatase 1 (PP1) has been demonstrated. We addressed whether the protein phosphatase 2A (PP2A) that is abundant in the brain could be involved in the regulation of CaMKIIα. CaMKIIα was associated with the catalytic subunit of PP2A (PP2Ac) and α4, a regulator of PP2A. To investigate whether α4 plays an important role in the CNS, we established a neuron specific Cre transgenic mouse and a neuron specific α4 deficient mouse (N-α4 KO mouse). This N-α4 KO mouse showed impaired learning and memory in a water maze and also shuttle-box avoidance test. The activity of CaMKIIα also increased in hippocampus. An overexpression of α4 in the neuronal cell line demonstrated the activity of CaMKIIα to be regulated by α4. α4 and PP2Ac were localized in the cytoplasm but not in the postsynaptic density (PSD), thus suggesting that the dephosphorylation of CaMKIIα by α4/PP2Ac occurred in the cytoplasm. These results suggest that α4 and PP2A may thus play an important role in CaMKIIα regulation and thereby also influence learning.