Persistent phosphorylation by protein kinase Mzeta maintains late-phase long-term potentiation

Protein kinase Mzeta (PKMzeta), an autonomously active atypical PKC isoform, is both necessary and sufficient for enhanced synaptic transmission during long-term potentiation (LTP) maintenance. LTP, however, evolves through several temporal phases, which may be mediated by distinct molecular mechanisms of potentiation. Here, we determined the specific phase of LTP maintained by PKMzeta. Using a selective, cell-permeable zeta-pseudosubstrate inhibitor at concentrations that block potentiation produced by postsynaptic perfusion of PKMzeta, we inhibited PKMzeta activity at various times after tetanization of Schaffer collateral/commissural-CA1 synapses. Inhibition of PKMzeta did not affect baseline AMPA receptor-mediated synaptic transmission or an early phase of LTP. In contrast, the inhibitor reversed established LTP when applied 1, 3, or 5 h after tetanic stimulation. Control nontetanized pathways within the hippocampal slices were unaffected. An inactive scrambled version of the peptide had no effect on LTP. Thus, persistent, increased phosphorylation by PKMzeta specifically maintains the late phase of LTP.