Involvement of NMDAR2A tyrosine phosphorylation in depression-related behaviour

Sachiko Taniguchi, Takanobu Nakazawa, Asami Tanimura, Yuji Kiyama, Tohru Tezuka, Ayako M. Watabe, Norikazu Katayama, Kazumasa Yokoyama, Takeshi Inoue, Hiroko Izumi-Nakaseko, Shigeru Kakuta, Katsuko Sudo, Yoichiro Iwakura, Hisashi Umemori, Takafumi Inoue, Niall P. Murphy, Kouichi Hashimoto, Masanobu Kano, Toshiya Manabe, Tadashi Yamamoto

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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.

Original languageEnglish
Pages (from-to)3717-3729
Number of pages13
JournalEMBO Journal
Volume28
Issue number23
DOIs
Publication statusPublished - 2009 Dec 1

Keywords

  • DARPP-32
  • Depression-related behaviour
  • NMDA receptor
  • Src
  • Tyrosine phosphorylation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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  • Cite this

    Taniguchi, S., Nakazawa, T., Tanimura, A., Kiyama, Y., Tezuka, T., Watabe, A. M., Katayama, N., Yokoyama, K., Inoue, T., Izumi-Nakaseko, H., Kakuta, S., Sudo, K., Iwakura, Y., Umemori, H., Inoue, T., Murphy, N. P., Hashimoto, K., Kano, M., Manabe, T., & Yamamoto, T. (2009). Involvement of NMDAR2A tyrosine phosphorylation in depression-related behaviour. EMBO Journal, 28(23), 3717-3729. https://doi.org/10.1038/emboj.2009.300