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The Journal of Neuroscience, June 10, 2009, 29(23):7607-7618; doi:10.1523/JNEUROSCI.0707-09.2009

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Cellular/Molecular
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

Yoko Yamagata,^1,2,3 Shizuka Kobayashi,⁴ Tatsuya Umeda,⁵ Akihiro Inoue,⁵ Hiroyuki Sakagami,⁶ Masahiro Fukaya,⁷ Masahiko Watanabe,⁷ Nobuhiko Hatanaka,⁸ Masako Totsuka,³ Takeshi Yagi,¹⁰ Kunihiko Obata,⁹ Keiji Imoto,^1,2 Yuchio Yanagawa,^3,11 Toshiya Manabe,^3,4 and Shigeo Okabe¹²

¹Department of Information Physiology, National Institute for Physiological Sciences, and ²The Graduate University for Advanced Studies (SOKENDAI), Okazaki 444-8787, Japan, ³Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan, ⁴Division of Neuronal Network, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan, ⁵Department of Cell Biology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan, ⁶Department of Anatomy, Kitasato University School of Medicine, Sagamihara 228-8555, Japan, ⁷Department of Anatomy, Hokkaido University School of Medicine, Sapporo 060-8638, Japan, ⁸Division of System Neurophysiology and ⁹Laboratory of Neurochemistry, National Institute for Physiological Sciences, Okazaki 444-8585, Japan, ¹⁰Graduate School of Frontier Biosciences, Osaka University, Suita 565-0871, Japan, ¹¹Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan, and ¹²Department of Cellular Neurobiology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan

Correspondence should be addressed to Dr. Yoko Yamagata, Department of Information Physiology, National Institute for Physiological Sciences, Myodaiji, Okazaki 444-8787, Japan. Email: yamagata{at}nips.ac.jp

Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) 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 CaMKII, respectively, in the induction of long-term potentiation (LTP) and hippocampus-dependent learning. However, kinase activity of CaMKII, the most essential enzymatic function, has not been genetically dissected yet. Here, we generated a novel CaMKII 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 CaMKII (K42R) mice, kinase activity was reduced to the same level as in CaMKII-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 CaMKII was preserved. In addition, CaMKII (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 CaMKII is a common critical gate controlling structural, functional, and behavioral expression of synaptic memory.

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Received Feb. 11, 2009; revised April 23, 2009; accepted April 30, 2009.

Correspondence should be addressed to Dr. Yoko Yamagata, Department of Information Physiology, National Institute for Physiological Sciences, Myodaiji, Okazaki 444-8787, Japan. Email: yamagata{at}nips.ac.jp

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