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

Changchi Hsieh, Panayiotis Tsokas, Alejandro Grau-Perales, Edith Lesburguères, Joseph Bukai, Kunal Khanna, Joelle Chorny, Ain Chung, Claudia Jou, Nesha S. Burghardt, Christine A. Denny, Rafael E. Flores-Obando, Benjamin Rush Hartley, Laura Melissa Rodríguez Valencia, A. Iván Hernández, Peter J. Bergold, James E. Cottrell, Juan Marcos Alarcon, André Antonio Fenton, Todd Charlton Sacktor

Research output: Contribution to journalArticlepeer-review


PKMζ 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, PKMζ is persistently activated through sustained increases in protein expression of the kinase. Therefore, visualizing increases in PKMζ 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 PKMζ-null mice, we examined the amount and distribution of PKMζ 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, PKMζ increases in the pyramidal cell body and stimulated dendritic layers of CA1 for at least 2 hr. During spatial memory storage, PKMζ 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 PKMζ 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 PKMζ trace the molecular mechanism of LTP maintenance and thus the sites of information storage within brain circuitry during long-term memory.

Original languageEnglish (US)
Pages (from-to)6795-6814
Number of pages20
JournalEuropean Journal of Neuroscience
Issue number8
StatePublished - Oct 2021


  • ArcCreER x ChR2-eYFP mice
  • ArcCreER x eYFP mice
  • PKM-zeta
  • PKMzeta
  • memory storage

ASJC Scopus subject areas

  • General Neuroscience


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