Long-term potentiation (LTP) is the form of synaptic plasticity most commonly associated with learning and memory. Studies using
protein kinase inhibitors have suggested functional roles for several
kinases in the induction of LTP in the CA1 region of the hippocampus, though the precise role of any given
kinase has yet to be fully established. Here we report that the selective
calcium/calmodulin-dependent protein kinase (CaMK) inhibitor
KN-62 has two distinct actions on LTP. As reported previously,
KN-62 (3 microM) prevented the induction of LTP. Here we show that
KN-62 also prevents the setting of a molecular switch, initiated by the synaptic activation of (S)-alpha-methyl-4-carboxyphenylglycine (MCPG)-sensitive metabotropic
glutamate (mGlu) receptors. There are two aspects of this work which might be considered surprising. First, the setting of the molecular switch was prevented by a concentration of
KN-62 (1 microM) subthreshold for the inhibition of the induction of LTP per se. Second, the setting of the molecular switch, by the delivery of a
tetanus (100 Hz, 1 s) in the presence of a specific
NMDA receptor antagonist (R)-2-amino-5-phosphonopentanoate (AP5), reduced the sensitivity of LTP to
KN-62, such that at a concentration of 3 microM it no longer blocked induction (though
at 10 microM it did). This conditioning effect of a
tetanus, delivered in the presence of AP5, was prevented by MCPG (200 microM). These data reveal unexpected complexities in the involvement of KN-62-sensitive processes (presumably
CaMKII) in the induction of LTP. They suggest that activation of KN-62-sensitive processes leads to (at least) two phosphorylation steps with fundamentally different roles in synaptic plasticity within a single synapse. They also raise the possibility that
CaMKII is an integral part of the MCPG-sensitive molecular switch mechanism.