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The Journal of Neuroscience, October 1, 2008, 28(40):9910-9919; doi:10.1523/JNEUROSCI.2625-08.2008

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Neurobiology of Disease
Upregulation of Calcium/Calmodulin-Dependent Protein Kinase IV Improves Memory Formation and Rescues Memory Loss with Aging

Hotaka Fukushima,¹ Ryouta Maeda,¹ Ryousuke Suzuki,¹ Akinobu Suzuki,¹ Masanori Nomoto,¹ Hiroki Toyoda,² Long-Jun Wu,² Hui Xu,² Ming-Gao Zhao,² Kenji Ueda,¹ Aya Kitamoto,¹ Nori Mamiya,¹ Taro Yoshida,¹ Seiichi Homma,¹ Shoichi Masushige,¹ Min Zhuo,² and Satoshi Kida^1,3

¹Department of Bioscience, Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo 156-8502, Japan, ²Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8, and ³Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan

Correspondence should be addressed to either of the following: Min Zhuo, Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, University of Toronto, Toronto, Canada M5S 1A8, Email: min.zhuo{at}utoronto.ca; or Satoshi Kida, Department of Bioscience, Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo 156-8502, Japan, Email: kida{at}nodai.ac.jp

Previous studies have suggested that calcium/calmodulin-dependent protein kinase IV (CaMKIV) functions as a positive regulator for memory formation and that age-related memory deficits are the result of dysfunctional signaling pathways mediated by cAMP response element-binding protein (CREB), the downstream transcription factor of CaMKIV. Little is known, however, about the effects of increased CaMKIV levels on the ability to form memory in adult and aged stages. We generated a transgenic mouse overexpressing CaMKIV in the forebrain and showed that the upregulation of CaMKIV led to an increase in learning-induced CREB activity, increased learning-related hippocampal potentiation, and enhanced consolidation of contextual fear and social memories. Importantly, we also observed reduced hippocampal CaMKIV expression with aging and a correlation between CaMKIV expression level and memory performance in aged mice. Genetic overexpression of CaMKIV was able to rescue associated memory deficits in aged mice. Our findings suggest that the level of CaMKIV expression correlates positively with the ability to form long-term memory and implicate the decline of CaMKIV signaling mechanisms in age-related memory deficits.

Key words: aging; CaMKIV; hippocampus; memory consolidation; transgenic mice; CREB

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Received June 9, 2008; revised Aug. 2, 2008; accepted Aug. 18, 2008.

Correspondence should be addressed to either of the following: Min Zhuo, Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, University of Toronto, Toronto, Canada M5S 1A8, Email: min.zhuo{at}utoronto.ca; or Satoshi Kida, Department of Bioscience, Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo 156-8502, Japan, Email: kida{at}nodai.ac.jp

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