PKM-ζ is not required for hippocampal synaptic plasticity, learning and memory
Open accessAbstract
Long-term potentiation (LTP), a well-characterized form of synaptic plasticity, has long been postulated as a cellular correlate of learning and memory. Although LTP can persist for long periods of time, the mechanisms underlying LTP maintenance, in the midst of ongoing protein turnover and synaptic activity, remain elusive. Sustained activation of the brain-specific protein kinase C (PKC) isoform protein kinase M-ζ (PKM-ζ) has been reported to be necessary for both LTP maintenance and long-term memory. Inhibiting PKM-ζ activity using a synthetic zeta inhibitory peptide (ZIP) based on the PKC-ζ pseudosubstrate sequence reverses established LTP in vitro and in vivo. More notably, infusion of ZIP eliminates memories for a growing list of experience-dependent behaviours, including active place avoidance, conditioned taste aversion, fear conditioning and spatial learning. However, most of the evidence supporting a role for PKM-ζ in LTP and memory relies heavily on pharmacological inhibition of PKM-ζ by ZIP. To further investigate the involvement of PKM-ζ in the maintenance of LTP and memory, we generated transgenic mice lacking PKC-ζ and PKM-ζ. We find that both conventional and conditional PKC-ζ/PKM-ζ knockout mice show normal synaptic transmission and LTP at Schaffer collateral-CA1 synapses, and have no deficits in several hippocampal-dependent learning and memory tasks. Notably, ZIP still reverses LTP in PKC-ζ/PKM-ζ knockout mice, indicating that the effects of ZIP are independent of PKM-ζ.
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Positive feedback loops that maintain key kinases and other molecules in persistently active states at strengthened synapses may also contribute to long-term memory storage.
“Positive feedback loops that maintain key kinases and other molecules in persistently active states at strengthened synapses may also contribute to such long-term memory storage75–79.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [78]
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- Authors
- Volk, L. J., Bachman, J. L., Johnson, R., Yu, Y., & Huganir, R. L.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Huganir, Richard L.
- Venue
- Nature
- Published
- 2013-01-02
- Volume
- 493
- Issue
- 7432
- Pages
- 420-423
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3830948
- OpenAlex
- W2063017515
- Cited by
- 310
- References
- 28
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 15 · 2023: 7 · 2022: 10 · 2021: 17 · 2020: 10 · 2019: 24 · 2018: 22 · 2017: 33 · 2016: 33 · 2015: 37 · 2014: 37 · 2013: 50 · 2012: 1
- FWCI
- 25.67
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Institute of Mental Health (T32MH15330, T32MH015330)
- National Eye Institute (T32EY017203)
- National Institute of Neurological Disorders and Stroke (NS36715, P30NS050274, R01NS036715, R37NS036715)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- PKM, protein kinase M, long-term potentiation, synaptic plasticity, learning and memory, protein kinase C, LTP maintenance, memory maintenance, hippocampus, memory formation, fear conditioning, spatial learning, conditioned taste aversion, place avoidance, PKCδ, protein kinase C epsilon
- MeSH terms
- Protein Kinase C zeta, Animals, Avoidance Learning, Behavior, Animal, Conditioning, Classical, Fear, Female, Hippocampus, Isoenzymes, Male, Synaptic Transmission, Neuronal Plasticity, Protein Kinase C, Synapses, Long-Term Potentiation, Mice, Knockout, Mice, Lipopeptides, Memory, Long-Term, Cell-Penetrating Peptides
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