Mitogen-activated protein kinase regulates early phosphorylation and delayed expression of Ca2+/calmodulin-dependent protein kinase II in long-term potentiation

Activation of mitogen-activated protein kinase (MAPK) and Ca2+/calmodulin-d ependent protein kinase II (CaMKII) are required for numerous forms of neur onal plasticity, including long-term potentiation (LTP). We induced LTP in rat hippocampal area CA1 using theta-pulse stimulation (TPS) paired with be ta -adrenergic receptor activation [isoproterenol (ISO)], a protocol that m ay be particularly relevant to normal patterns of hippocampal activity duri ng learning. This stimulation resulted in a transient phosphorylation of p4 2 MAPK, and the resulting LTP was MAPK dependent. In addition, CaMKII was r egulated in two, temporally distinct ways after TPS-ISO: a transient rise i n the fraction of phosphorylated CaMKII and a subsequent persistent increas e in CaMKII expression. The increases in MAPK and CaMKII phosphorylation we re strongly colocalized in the dendrites and cell bodies of CA1 pyramidal c ells, and both the transient phosphorylation and delayed expression of CaMK II were prevented by inhibiting p42/p44 MAPK. These results establish a nov el bimodal regulation of CaMKII by MAPK, which may contribute to both post- translational modification and increased gene expression.