Inhibition of protein kinase C blocks two components of LTP persistence, leaving initial potentiation intact

Patricia A. Colley, Fwu Shan Sheu, Aryeh Routtenberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

97 Scopus citations


Protein kinase C (PKC) activity is increased following hippocampal long-term potentiation (LTP; Akers et al., 1986). A similar increase in PKC activity is measured following the induction of a long-lasting potentiation with abbreviated high-frequency stimulation (HFS) in combination with PKC-activating phorbol esters (Colley et al., 1989). Because phorbol esters have no effect on the initial potentiation produced with HFS, and because PKC activity appears to be related to the persistence of LTP and not to the initial change, we concluded that PKC regulates a post-initiation component of LTP. To define the time domain in which PKC activation is necessary for LTP, we studied the effect of the PKC inhibitors polymyxin B (PMXB) and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) micropressure ejected at different time points before and after the induction of LTP. LTP was produced in intact rats with HFS of the perforant path, and inhibitor ejections were made in the molecular layer of the dentate gyrus. PMXB, which at lower doses is a selective inhibitor of PKC, had no effect on initial potentiation, yet caused decay of the potentiated response to baseline within 2 hr. Decay occurred when PMXB was ejected 15 min before and 15 and 30 min after HFS. PMXB, at either low or high doses, was ineffective in blocking LTP persistence at time points greater than 30 min after HFS. Low doses of H-7 produced similar effects to those of PMXB. However, in contrast to a high dose of PMXB, a high dose of H-7 inhibited the persistence of LTP when delivered 240 min after HFS. A decrease in the in vitro phosphorylation of the PKC substrate protein F1 in animals that showed a decay of LTP following PMXB or H-7 ejection suggests that PKC was inhibited in vivo. We propose a model of LTP that consists of 3 separable phases: (1) initial potentiation (0-5 min), which does not require PKC activation; (2) a PKC-regulated persistence phase (5-60 min) related to synaptic modification; and (3) a second PKC-regulated persistence phase (>60 min), which is dependent on protein synthetic processes.

Original languageEnglish (US)
Pages (from-to)3353-3360
Number of pages8
JournalJournal of Neuroscience
Issue number10
StatePublished - 1990

ASJC Scopus subject areas

  • Neuroscience(all)


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