Kinase-Dead Knock-In Mouse Reveals an Essential Role of Kinase Activity of Ca2+/Calmodulin-Dependent Protein Kinase II in Dendritic Spine Enlargement, Long-Term Potentiation, and Learning
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Ca2+/calmodulin-dependent protein kinase IIalpha (CaMKIIalpha) is an essential mediator of activity-dependent synaptic plasticity that possesses multiple protein functions. So far, the autophosphorylation site-mutant mice targeted at T286 and at T305/306 have demonstrated the importance of the autonomous activity and Ca2+/calmodulin-binding capacity of CaMKIIalpha, respectively, in the induction of long-term potentiation (LTP) and hippocampus-dependent learning. However, kinase activity of CaMKIIalpha, the most essential enzymatic function, has not been genetically dissected yet. Here, we generated a novel CaMKIIalpha knock-in mouse that completely lacks its kinase activity by introducing K42R mutation and examined the effects on hippocampal synaptic plasticity and behavioral learning. In homozygous CaMKIIalpha (K42R) mice, kinase activity was reduced to the same level as in CaMKIIalpha-null mice, whereas CaMKII protein expression was well preserved. Tetanic stimulation failed to induce not only LTP but also sustained dendritic spine enlargement, a structural basis for LTP, at the Schaffer collateral-CA1 synapse, whereas activity-dependent postsynaptic translocation of CaMKIIalpha was preserved. In addition, CaMKIIalpha (K42R) mice showed a severe impairment in inhibitory avoidance learning, a form of memory that is dependent on the hippocampus. These results demonstrate that kinase activity of CaMKIIalpha is a common critical gate controlling structural, functional, and behavioral expression of synaptic memory.
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Both sLTP and LTP are greatly diminished in a CaMKII-dead mutant (K42K or K42M), despite its translocation.
“In support of these results, both sLTP (379) and LTP (121, 379) are greatly diminished in a CaMKII-dead mutant (K42K or K42M), despite its translocation.”
From Synaptic memory and CaMKII (2023) · cites this paper as [379]
The sections on tetanus-induced spine structural plasticity and LTP report severely impaired spine enlargement and LTP, while the postsynaptic-dynamics section reports preserved translocation. The mutant studied is K42R, however, not the K42K or K42M mutant named in the claim. Page numbers are unavailable in our copy. (LLM, conf=0.88)
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A Role for Dendritic Translation of CaMKIIα mRNA in Olfactory Plasticity
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In memoriam: John Lisman – commentaries on CaMKII as a memory molecule
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The CaMKII K42M and K42R mutations are equivalent in suppressing kinase activity and targeting
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Formation of long-term memory without short-term memory revealed by CaMKII inhibition
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CaMKII Requirement for in Vivo Insular Cortex LTP Maintenance and CTA Memory Persistence
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Activity-Dependent Stabilization of Nascent Dendritic Spines Requires Nonenzymatic CaMKIIα Function
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- Authors
- Yamagata, Y., Kobayashi, S., Umeda, T., Inoue, A., Sakagami, H., Fukaya, M., Watanabe, M., Hatanaka, N., Totsuka, M., Yagi, T., Obata, K., Imoto, K., Yanagawa, Y., Manabe, T., & Okabe, S.
- Affiliations
- National Institute for Physiological Sciences (JP)
- Institute of Medical Science, The University of Tokyo (JP)
- Tokyo Medical and Dental University (JP)
- Kitasato University (JP)
- Hokkaido University (JP)
- Japan Science and Technology Agency (JP)
- The University of Osaka (JP)
- The Graduate University for Advanced Studies, SOKENDAI (JP)
- Gunma University (JP)
- The University of Tokyo (JP)
- ORCID
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-06-10
- Volume
- 29
- Issue
- 23
- Pages
- 7607-7618
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6665418
- OpenAlex
- W2049217965
- Cited by
- 146
- References
- 53
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 9 · 2023: 9 · 2022: 10 · 2021: 12 · 2020: 6 · 2019: 9 · 2018: 8 · 2017: 11 · 2016: 3 · 2015: 8 · 2014: 8 · 2013: 7 · 2012: 12
- FWCI
- 4.43
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Novartis Foundation
- Brain Science Foundation
- NOVARTIS Foundation (Japan) for the Promotion of Science
- Japan Society for the Promotion of Science
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- CaMKIIα, kinase activity, knock-in mice, long-term potentiation, synaptic plasticity, hippocampus-dependent learning, passive avoidance, Schaffer collateral-CA1 synapses, synaptic memory
- MeSH terms
- Animals, Avoidance Learning, Cells, Cultured, Female, Hippocampus, Male, Mice, Transgenic, Neuronal Plasticity, Neurons, Synapses, Long-Term Potentiation, Mice, Knockout, Excitatory Postsynaptic Potentials, Mutation, Missense, Dendritic Spines, Mice, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Gene Knock-In Techniques, In Vitro Techniques
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