Cited by 208Neuroscience and Neuropharmacology ResearchMemory and Neural MechanismsNeural dynamics and brain function

Chapter 2 PKMζ, LTP maintenance, and the dynamic molecular biology of memory storage

Sacktor, Todd Charlton·2008·Progress in Brain Research

Abstract

How memories persist is a fundamental neurobiological question. The most commonly studied physiological model of memory is long-term potentiation (LTP). The molecular mechanisms of LTP can be divided into two phases: induction, triggering the potentiation; and maintenance, sustaining the potentiation over time. Although many molecules participate in induction, very few have been implicated in the mechanism of maintenance. Understanding maintenance, however, is critical for testing the hypothesis that LTP sustains memory storage in the brain. Only a single molecule has been found both necessary and sufficient for maintaining LTP--the brain-specific, atypical PKC isoform, protein kinase Mzeta (PKMzeta). Although full-length PKC isoforms respond to transient second messengers, and are involved in LTP induction, PKMzeta is a second messenger-independent kinase, consisting of the independent catalytic domain of PKCzeta, and is persistently active to sustain LTP maintenance. PKMzeta is produced by a unique PKMzeta mRNA, which is generated by an internal promoter within the PKCzeta gene and transported to the dendrites of neurons. LTP induction increases new PKMzeta synthesis, and the increased level of PKMzeta then enhances synaptic transmission by doubling the number of postsynaptic AMPA receptors (AMPAR) through GluR2 subunit-mediated trafficking of the receptors to the synapse. PKMzeta mediates synaptic potentiation specifically during the late-phase of LTP, as PKMzeta inhibitors can reverse established LTP when applied several hours after tetanization in hippocampal slices or 1 day after tetanization in vivo. These studies set the stage for testing the hypothesis that the mechanism of LTP maintenance sustains memory storage. PKMzeta inhibition in the hippocampus after learning eliminates the retention of spatial memory. Once the PKMzeta inhibitor has been eliminated, the memory is still erased, but new spatial memories can be learned and stored. Similar results are found for conditioned taste aversion when the inhibitor is injected in the insular neocortex. Thus PKMzeta is the first molecule found to be a component of the long-term memory trace.

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Crossref · 10.1016/s0079-6123(07)00002-7

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  • PKA, CaMKIV, protein kinase M-z, and ERK, as well as other signaling molecules, initiate protein synthesis either locally in dendrites from prefabricated mRNA or by nuclear transcription.

    “PKA, CaMKIV, protein kinase M-z, and extracellular signal -regulated kinase (ERK), as well as other signaling molecules, initiate protein synthesis either locally in the dendrites from prefabricated mRNA or by nuclear transcription (Sacktor 2008).”
  • Nuclear transcription involved in LTP maintenance involves interactions with transcription factors, including CREB.

    “The latter involves interactions with transcription factors, including cAMP response element -binding protein (CREB).”
  • The maintenance of the change in synaptic strength during LTP is protein synthesis-dependent.

    “Not only does long-term plasticity cause structural changes in synapses, but the maintenance of the change in synaptic strength during LTP is protein synthesis -dependent.”
  • The kinase PKMζ is engaged at ≥1 h after induction and then contributes to maintenance of LTP.

    “several studies have shown that the kinase PKMζ is engaged at ≥1 h after induction and then contributes to maintenance of LTP (39).”

    From Synaptic evidence for the efficacy of spaced learning (2012) · cites this paper as [39]

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Authors
Sacktor, T. C.
Affiliations
State University of New York (US)
Corresponding author
Sacktor, Todd Charlton
Venue
Progress in Brain Research
Publisher
Elsevier
Published
2008
Volume
169
Pages
27-40
ISSN
0079-6123 (ISSN-L)
OpenAlex
W1550519555
Cited by
208
References
86
Citations by year
2026: 2 · 2025: 6 · 2024: 1 · 2023: 1 · 2022: 4 · 2021: 2 · 2020: 5 · 2019: 8 · 2018: 6 · 2017: 8 · 2016: 9 · 2015: 14 · 2014: 17 · 2013: 25 · 2012: 24
FWCI
29.63
Type
book chapter
Language
en
Open access
closed
Locations
  • Progress in brain research (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
Keywords
PKMzeta, long-term potentiation, LTP maintenance, memory storage, protein kinase C zeta, dendritic mRNA transport, AMPA receptor trafficking, GluR2 subunit, synaptic potentiation, late-phase LTP, spatial memory, conditioned taste aversion, hippocampus, memory traces
MeSH terms
Animals, Hippocampus, Humans, Memory, Molecular Biology, Protein Kinase C, Long-Term Potentiation, Excitatory Postsynaptic Potentials, Rats

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