Altered Actions of Memantine and NMDA-Induced Currents in a New Grid2-Deleted Mouse Line

Genes

Ayako Kumagai¹  Akira Fujita⁵  Tomoki Yokoyama⁵  Yuki Nonobe⁵  Yasuhiro Hasaba⁵  Tsutomu Sasaki⁴  Yumi Itoh¹  Minako Koura²  Osamu Suzuki²  Shigeki Adachi³  Haruko Ryo³  Arihiro Kohara⁸  Lokesh P. Tripathi⁶  Masato Sanosaka¹  Toshiki Fukushima⁵  Hiroyuki Takahashi⁵  Kazuo Kitagawa⁴  Yasuo Nagaoka⁷  Hidehisa Kawahara⁷  Kenji Mizuguchi⁶  Taisei Nomura³  Junichiro Matsuda²  Toshihide Tabata⁵ 

[1] Laboratory of Cell Signaling and Metabolic Disease, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan; E-Mails:;Laboratory of Animal Models for Human Diseases, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan; E-Mails:;Nomura Project, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan; E-Mails:;Department of Neurology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; E-Mails:;Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan; E-Mails:;Laboratory of Bioinformatics, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan; E-Mails:;Department of Life Science and Biotechnology, Kansai University, Suita, Osaka 564-8680, Japan; E-Mails:;Laboratory of Cell Cultures, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan; E-Mail:

关键词: GRID2;    GluRδ2;    memantine;    NMDA receptor;    cerebellum;   

DOI  :  10.3390/genes5041095

来源: mdpi

【 摘 要 】

Memantine is a non-competitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, and is an approved drug for the treatment of moderate-to-severe Alzheimer’s disease. We identified a mouse strain with a naturally occurring mutation and an ataxic phenotype that presents with severe leg cramps. To investigate the phenotypes of these mutant mice, we screened several phenotype-modulating drugs and found that memantine (10 mg/kg) disrupted the sense of balance in the mutants. Moreover, the mutant mice showed an attenuated optokinetic response (OKR) and impaired OKR learning, which was also observed in wild-type mice treated with memantine. Microsatellite analyses indicated that the Grid2 gene-deletion is responsible for these phenotypes. Patch-clamp analysis showed a relatively small change in NMDA-dependent current in cultured granule cells from Grid2 gene-deleted mice, suggesting that GRID2 is important for correct NMDA receptor function. In general, NMDA receptors are activated after the activation of non-NMDA receptors, such as AMPA receptors, and AMPA receptor dysregulation also occurs in Grid2 mutant mice. Indeed, the AMPA treatment enhanced memantine susceptibility in wild-type mice, which was indicated by balance sense and OKR impairments. The present study explores a new role for GRID2 and highlights the adverse effects of memantine in different genetic backgrounds.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.