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

Ca2+-dependent CaMKII alpha activation with autophosphorylation plays an essential role in learning and memory. The regulation of CaMKII alpha 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 CaMKII alpha. CaMKII alpha was associated with the catalytic subunit of PP2A (PP2Ac) and alpha 4, a regulator of PP2A. To investigate whether alpha 4 plays an important role in the CNS, we established a neuron specific Cre transgenic mouse and a neuron specific alpha 4 deficient mouse (N-alpha 4 KO mouse). This N-alpha 4 KO mouse showed impaired learning and memory in a water maze and also shuttle-box avoidance test. The activity of CaMKIIC alpha also increased in hippocampus. An overexpression of alpha 4 in the neuronal cell line demonstrated the activity of CaMKII alpha to be regulated by alpha A.alpha 4 and PP2Ac were localized in the cytoplasm but not in the postsynaptic density (PSD), thus suggesting that the dephosphorylation of CaMKII alpha by alpha 4/PP2Ac occurred in the cytoplasm. These results suggest that alpha 4 and PP2A may thus play an important role in CaMKII alpha regulation and thereby also influence learning. (c) 2006 Elsevier B.V. All rights reserved.