PKMzeta, LTP, and Memory

Most molecules implicated in memory are involved in neuronal signaling events during a brief time window lasting only minutes to hours after learning. Molecules involved in maintaining the storage of long-term memory for days to weeks have been unknown. Recently, the persistently active atypical protein kinase C (PKC) isoform, PKMzeta, has been identified as a potential component of the molecular mechanism maintaining both synaptic long-term potentiation (LTP), a physiological model for memory, and long-term memory, itself. Pharmacological or genetic manipulations decreasing PKMzeta activity in adult mice or rats disrupt established LTP and long-term memories. In contrast, constitutive PKMzeta knockout mice recruit a “back-up” maintenance mechanism for LTP, involving persistent activation of the most closely related gene-product — the other atypical PKC isoform, PKCiota/lambda. After initial memory consolidation in wild-type animals, increases of endogenous PKMzeta persist within specific circuits of the brain for weeks. Overexpressing PKMzeta enhances both new and established long-term memories. Thus, by targeting PKMzeta, for the first time established long-term memories can be erased, traced, or enhanced.