We show that α and βCaMKII are inversely regulated by activity in hippocampal neurons in culture: the α/β ratio shifts toward α during increased activity and β during decreased activity. The swing in ratio is ∼5-fold and may help tune the CaMKII holoenzyme to changing intensities of Ca2+ signaling. The regulation of CaMKII levels uses distinguishable pathways, one responsive to NMDA receptor blockade that controls αCaMKII alone, the other responsive to AMPA receptor blockade and involving βCaMKII and possibly further downstream effects of βCaMKII on αCaMKII. Overexpression of αCaMKII or βCaMKII resulted in opposing effects on unitary synaptic strength as well as mEPSC frequency that could account in part for activity-dependent effects observed with chronic blockade of AMPA receptors. Regulation of CaMKII subunit composition may be important for both activity-dependent synaptic homeostasis and plasticity.
