In area CA1 of the hippocampus, the induction of long term potentiation (LTP) requires activation of either N-methyl-D-aspartate receptors (NMDA receptor-dependent LTP) or voltage-gated Ca2+ channels (NMDA receptor- independent LTP). We have investigated biochemical sequelae of NMDA receptor- independent LTP induction. We find that a persistent increase in second messenger-independent protein kinase C activity is associated with the maintenance phase of NMDA receptor-independent LTP. This increase in protein kinase C activity is prevented by blocking LTP with nifedipine, a Ca2+ channel antagonist, or kynurenic acid, a nonselective glutamate receptor antagonist. Additionally, we find an increase in the catalytic fragment of protein kinase C (PKM) in the maintenance phase of NMDA receptor-independent LTP, indicating that proteolytic activation of protein kinase C may account for its autonomous activation. This increase in the catalytic fragment of protein kinase C is also prevented by blocking LTP induction. These results are the first to demonstrate that persistent protein kinase C activation is a possible mechanism for the maintenance of NMDA receptor-independent LTP.