PKMζ traces hippocampal LTP maintenance and spatial long-term memory

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 protein kinases that are transiently stimulated by second messengers, PKM{zeta} is persistently activated through sustained increases in kinase protein expression. 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 h. During spatial memory storage, PKM{zeta} increases in CA1 pyramidal cells for at least 1 month, paralleling the persistence of the memory. The subset of CA1 pyramidal cells that are tagged by immediate early gene Arc-driven transcription of fluorescent proteins, whose expression increases during initial memory formation, also expresses the persistent increase of PKM{zeta} during memory storage. In the memory-tagged cells, the increased PKM{zeta} expression persists in dendritic compartments within stratum radiatum for 1 month, indicating the long-term storage of information in the CA3-to-CA1 pathway during remote spatial memory. 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.