Long-term potentiation (LTP), a persistent synaptic enhancement thought to be a substrate for memory1, can be divided into two phases: induction, triggering potentiation, and maintenance, sustaining it over time1,2. Many postsynaptic events are implicated in induction, including N-methyl-D-aspartate receptor (NMDAR) activation, calcium increases and stimulation of several protein kinases1; in contrast, the mechanism maintaining LTP is not yet characterized1. Here we show the constitutively active form of an atypical protein kinase C (PKC) isozyme, protein kinase M zeta (PKMζ), is necessary and sufficient for LTP maintenance.
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Supported by New York City Council Speaker's Fund for Biomedical Research (D.S.F.L.) and NIMH (L.S.B. and T.C.S.).
Persistent phosphorylation by PKMζ is necessary for LTP maintenance. (a) Staurosporine (100 nM in 0.001% DMSO) applied prior to the tetanic stimulation blocked the induction of LTP. Pooled field recording data are mean ± SEM of 4 experiments. (b) Representative field potential traces showing 1 min pretetanus, 1 hr posttetanus (immediately prior to drug application), and 5 hr posttetanus. Above, staurosporine (100 nM in 0.001% DMSO); center, chelerythrine (1 µM in 0.001% DMSO); below, myristoylated ζ-pseudosubstrate peptide (1 µM). For data presented in Fig. 3, one-way ANOVA showed significant differences among DMSO alone, staurosporine, chelerythrine, and ζ-pseudosubstrate peptide, 4 hr post-application [F(3, 14) = 10.11, p = 0.0008]. Post hoc unpaired t-test showed significant differences for both chelerythrine and ζ-pseudosubstrate peptide compared to both DMSO and staurosporine (p < 0.01). No significant differences were observed between DMSO and staurosporine, and between chelerythrine and ζ-pseudosubstrate peptide. Staurosporine effectively inhibited conventional PKCα, novel PKCε, and CaMKII at low nanomolar concentrations, but was ineffective on PKMζ up to 100 nM (n = 3; the SEM, not shown for clarity in Fig. 3, were less than 30% of the means for all data points; p < 0.02, Wilcoxon's independent samples test, PKMζ compared to PKCα, PKCε and CaMKII). Chelerythrine inhibited PKMζ at lower concentrations than that required to inhibit PKCα, PKCε, and CaMKII (n = 3; p < 0.02). The myristoylated ζ-pseudosubstrate peptide selectively inhibited PKMζ relative to CaMKII (n = 3; p < 0.02).
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Infantile Amnesia Is Related to Developmental Immaturity of the Maintenance Mechanisms for Long-Term Potentiation
Molecular Neurobiology (2018)