Involvement of NMDAR2A tyrosine phosphorylation in depression‐related behaviour |
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| Authors: | Yuji Kiyama Ayako M Watabe Norikazu Katayama Kazumasa Yokoyama Takeshi Inoue Shigeru Kakuta Yoichiro Iwakura Hisashi Umemori Takafumi Inoue Niall P Murphy Kouichi Hashimoto Masanobu Kano Toshiya Manabe Tadashi Yamamoto |
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| Affiliation: | 1. Division of Neuronal Network, Institute of Medical Science, University of Tokyo, Tokyo, Japan;2. Division of Oncology, Institute of Medical Science, University of Tokyo, Tokyo, Japan;3. Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan;4. Molecular & Behavioral Neuroscience Institute and Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, USA;5. Department of Life Science and Bio‐science, Faculty of Science and Engineering, Waseda University, Tokyo, Japan;6. Hatos Center for Neuropharmacology, Department of Psychiatry and Biobehavioral Sciences, UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA;7. Department of Neurophysiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan;8. Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi, Japan;9. Laboratory of Molecular Biology, NCI, National Institutes of Health, Bethesda, MD, USA |
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| Abstract: | Major depressive and bipolar disorders are serious illnesses that affect millions of people. Growing evidence implicates glutamate signalling in depression, though the molecular mechanism by which glutamate signalling regulates depression‐related behaviour remains unknown. In this study, we provide evidence suggesting that tyrosine phosphorylation of the NMDA receptor, an ionotropic glutamate receptor, contributes to depression‐related behaviour. The NR2A subunit of the NMDA receptor is tyrosine‐phosphorylated, with Tyr 1325 as its one of the major phosphorylation site. We have generated mice expressing mutant NR2A with a Tyr‐1325‐Phe mutation to prevent the phosphorylation of this site in vivo. The homozygous knock‐in mice show antidepressant‐like behaviour in the tail suspension test and in the forced swim test. In the striatum of the knock‐in mice, DARPP‐32 phosphorylation at Thr 34, which is important for the regulation of depression‐related behaviour, is increased. We also show that the Tyr 1325 phosphorylation site is required for Src‐induced potentiation of the NMDA receptor channel in the striatum. These data argue that Tyr 1325 phosphorylation regulates NMDA receptor channel properties and the NMDA receptor‐mediated downstream signalling to modulate depression‐related behaviour. |
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| Keywords: | DARPP‐32 depression‐related behaviour NMDA receptor Src tyrosine phosphorylation |
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