CAM KINASE-II IN LONG-TERM POTENTIATION

The observation that autophosphorylation converts CaM kinase II from t he Ca2+-dependent form to the Ca2+-independent form has led to specula tion that the formation of the Ca2+-independent form of the enzyme cou ld encode frequency of synaptic usage and serve as a molecular explana tion of ''memory''. In cultured rat hippocampal neurons, glutamate ele vated the Ca2+-independent activity of CaM kinase II through autophosp horylation, and this response was blocked by an NMDA receptor antagoni st, D-2-amino-5-phosphonopentanoate (AP5). In addition, we confirmed t hat high, but not low frequency stimulation, applied to two groups of CA1 afferents in the rat hippocampus, resulted in LTP induction with c oncomitant long-lasting increases in Ca2+-independent and total activi ties of CaM kinase II. In experiments with P-32-labeled hippocampal sl ices, the LTP induction in the CA1 region was associated with increase s in autophosphorylation of both alpha and beta subunits of CaM kinase II 1 h after LTP induction. Significant increases in phosphorylation of endogenous CaM kinase II substrates, synapsin I and microtubule-ass ociated protein 2 (MAP2), which are originally located in presynaptic and postsynaptic regions, respectively, were also observed in the same slice. All these changes were prevented when high frequency stimulati on was applied in the presence of AP5 or a calmodulin antagonist, calm idazolium. Furthermore, in vitro phosphorylation of the AMPA receptor by CaM kinase II was reported in the postsynaptic density and infusion of the constitutively active CaM kinase II into the hippocampal neuro ns enhanced kainate-induced response. These results support the idea t hat CaM kinase II contributes to the induction of hippocampal LTP in b oth postsynaptic and presynaptic regions through phosphorylation of ta rget proteins such as the AMPA receptor, MAP2 and synapsin I. (C) 1996 Elsevier Science Ltd.