title: Altered Actions of Memantine and NMDA-Induced Currents in a New Grid2-Deleted Mouse Line.
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.
authors.affiliation: Laboratory of Cell Signaling and Metabolic Disease, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. a-kumagai@nibio.go.jp.
authors.forename: Ayako
authors.initials: A
authors.lastname: Kumagai
authors.affiliation: Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan. fujita0153@gmail.com.
authors.forename: Akira
authors.initials: A
authors.lastname: Fujita
authors.affiliation: Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan. m1371119@ems.u-toyama.ac.jp.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Yokoyama
authors.affiliation: Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan. weather4519@gmail.com.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nonobe
authors.affiliation: Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan. takegoshiyoshihiro45@gmail.com.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hasaba
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. sasaki@medone.med.osaka-u.ac.jp.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Laboratory of Cell Signaling and Metabolic Disease, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. y-itou@nibio.go.jp.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Itoh
authors.affiliation: Laboratory of Animal Models for Human Diseases, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. koura@nibio.go.jp.
authors.forename: Minako
authors.initials: M
authors.lastname: Koura
authors.affiliation: Laboratory of Animal Models for Human Diseases, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. osuzuki@nibio.go.jp.
authors.forename: Osamu
authors.initials: O
authors.lastname: Suzuki
authors.affiliation: Nomura Project, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. sadachi@nibio.go.jp.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Adachi
authors.affiliation: Nomura Project, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. hryo@nibio.go.jp.
authors.forename: Haruko
authors.initials: H
authors.lastname: Ryo
authors.affiliation: Laboratory of Cell Cultures, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. kohara@nibio.go.jp.
authors.forename: Arihiro
authors.initials: A
authors.lastname: Kohara
authors.affiliation: Laboratory of Bioinformatics, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. lokesh@nibio.go.jp.
authors.forename: Lokesh P
authors.initials: LP
authors.lastname: Tripathi
authors.affiliation: Laboratory of Cell Signaling and Metabolic Disease, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. m-sanosaka@nibio.go.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Sanosaka
authors.affiliation: Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan. fookun3@gmail.com.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Fukushima
authors.affiliation: Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan. m1471114@ems.u-toyama.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. kitagawa@neurol.med.osaka-u.ac.jp.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kitagawa
authors.affiliation: Department of Life Science and Biotechnology, Kansai University, Suita, Osaka 564-8680, Japan. t010034@kansai-u.ac.jp.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Nagaoka
authors.affiliation: Department of Life Science and Biotechnology, Kansai University, Suita, Osaka 564-8680, Japan. t912436@kansai-u.ac.jp.
authors.forename: Hidehisa
authors.initials: H
authors.lastname: Kawahara
authors.affiliation: Laboratory of Bioinformatics, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. kenji@nibio.go.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Mizuguchi
authors.affiliation: Nomura Project, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. n5nomura@nibio.go.jp.
authors.forename: Taisei
authors.initials: T
authors.lastname: Nomura
authors.affiliation: Laboratory of Animal Models for Human Diseases, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. jmatsuda@nibio.go.jp.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Matsuda
authors.affiliation: Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan. ttabata@eng.u-toyama.ac.jp.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Tabata
authors.affiliation: Laboratory of Cell Signaling and Metabolic Disease, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan. takemori@nibio.go.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takemori