Distinct synaptic loci of Ca2+/calmodulin-dependent protein kinase II necessary for long-term potentiation and depression.

1. Extracellular bath application of the selective Ca2+/calmodulin-dependent kinase II (CaMKII) inhibitor KN-62 to hippocampal slices in vitro blocked the induction of long-term depression (LTD) by low-frequency Schaffer collateral stimulation (1 Hz/15 min) of the same concentration as has been shown previously to prevent induction of long-term potentiation (LTP) at these synapses. 2. In contrast, postsynaptic intracellular infusion of KN-62 into single CA1 pyramidal neurons did not prevent induction of LTD, although it was quite effective in blocking LTP. 3. We conclude that there is a presynaptic CaMKII that must be activated to induce LTD, whereas postsynaptic CaMKII stimulation is needed to evoke LTP. 4. Bath application of KN-62 also blocked depotentiation by low-frequency stimuli of previously induced LTP, suggesting that induction of depotentiation and de novo LTD may require the same CaMKII-dependent mechanisms.