Persistent increases of PKM zeta in memory-activated neurons trace LTP maintenance during spatial long-term memory storage

Abstract

PKM zeta is an autonomously active PKC isoform crucial for the maintenance of synaptic long-term potentiation (LTP) and long-term memory. Unlike other kinases that are transiently stimulated by second messengers, PKM zeta is persistently activated through sustained increases in protein expression of the kinase. Therefore, visualizing increases in PKM zeta expression during long-term memory storage might reveal the sites of its persistent action and thus the location of memory-associated LTP maintenance in the brain. Using quantitative immunohistochemistry validated by the lack of staining in PKM zeta-null mice, we examined the amount and distribution of PKM zeta in subregions of the hippocampal formation of wild-type mice during LTP maintenance and spatial long-term memory storage. During LTP maintenance in hippocampal slices, PKM zeta increases in the pyramidal cell body and stimulated dendritic layers of CA1 for at least 2 hr. During spatial memory storage, PKM zeta increases in CA1 pyramidal cells for at least 1 month, paralleling the persistence of the memory. During the initial expression of the memory, we tagged principal cells with immediate-early gene Arc promoter-driven transcription of fluorescent proteins. The subset of memory-tagged CA1 cells selectively increases expression of PKM zeta during memory storage, and the increase persists in dendritic compartments within stratum radiatum for 1 month, indicating long-term storage of information in the CA3-to-CA1 pathway. We conclude that persistent increases in PKM zeta trace the molecular mechanism of LTP maintenance and thus the sites of information storage within brain circuitry during long-term memory.