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Genes (Basel). 2014 Dec 11;5(4):1095-114. doi: 10.3390/genes5041095.

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

Author information

1
Laboratory of Cell Signaling and Metabolic Disease, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. a-kumagai@nibio.go.jp.
2
Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan. fujita0153@gmail.com.
3
Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan. m1371119@ems.u-toyama.ac.jp.
4
Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan. weather4519@gmail.com.
5
Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan. takegoshiyoshihiro45@gmail.com.
6
Department of Neurology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. sasaki@medone.med.osaka-u.ac.jp.
7
Laboratory of Cell Signaling and Metabolic Disease, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. y-itou@nibio.go.jp.
8
Laboratory of Animal Models for Human Diseases, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. koura@nibio.go.jp.
9
Laboratory of Animal Models for Human Diseases, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. osuzuki@nibio.go.jp.
10
Nomura Project, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. sadachi@nibio.go.jp.
11
Nomura Project, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. hryo@nibio.go.jp.
12
Laboratory of Cell Cultures, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. kohara@nibio.go.jp.
13
Laboratory of Bioinformatics, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. lokesh@nibio.go.jp.
14
Laboratory of Cell Signaling and Metabolic Disease, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. m-sanosaka@nibio.go.jp.
15
Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan. fookun3@gmail.com.
16
Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan. m1471114@ems.u-toyama.ac.jp.
17
Department of Neurology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. kitagawa@neurol.med.osaka-u.ac.jp.
18
Department of Life Science and Biotechnology, Kansai University, Suita, Osaka 564-8680, Japan. t010034@kansai-u.ac.jp.
19
Department of Life Science and Biotechnology, Kansai University, Suita, Osaka 564-8680, Japan. t912436@kansai-u.ac.jp.
20
Laboratory of Bioinformatics, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. kenji@nibio.go.jp.
21
Nomura Project, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. n5nomura@nibio.go.jp.
22
Laboratory of Animal Models for Human Diseases, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. jmatsuda@nibio.go.jp.
23
Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan. ttabata@eng.u-toyama.ac.jp.
24
Laboratory of Cell Signaling and Metabolic Disease, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. takemori@nibio.go.jp.

Abstract

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.

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