TRANSIENT ACTIVATION OF CYCLIC-AMP-DEPENDENT PROTEIN-KINASE DURING HIPPOCAMPAL LONG-TERM POTENTIATION

Long-term potentiation (LTP) in the hippocampus is a possible mechanis m for mammalian learning and memory in which protein kinases play crit ical roles. We have investigated the involvement of cyclic AMP depende nt protein kinase (PKA) in LTP by directly studying its activation. We developed an in vitro assay which is useful for selective and accurat e measurement of stimulus-induced changes in PKA activity in hippocamp al slices. PKA was transiently activated 2 and 10 min after delivery o f LTP-inducing stimuli in area CA1 of the hip pocampus. This activatio n did not persist during early or late phases of LTP, suggesting that the role of PKA is in the induction of LTP, not in its expression. LTP was not associated with any change in the total activity of PKA, cons istent with activation by cyclic AMP, as opposed to an increase in the amount or efficacy of the enzyme. The LTP-associated activation of PK A required stimulation of the N-methyl-D-aspartate (NMDA) subtype of g lutamate receptor, and bath application of NMDA was sufficient to acti vate PKA. Together, these results indicate that at the initiation of L TP, NMDA receptor stimulation leads to transient activation of PKA, an d support a role for PKA in the induction of LTP.