Altered Actions of Memantine and NMDA-Induced Currents in a New Grid2-Deleted Mouse Line
AbstractMemantine 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. View Full-Text
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Kumagai, A.; Fujita, A.; Yokoyama, T.; Nonobe, Y.; Hasaba, Y.; Sasaki, T.; Itoh, Y.; Koura, M.; Suzuki, O.; Adachi, S.; Ryo, H.; Kohara, A.; Tripathi, L.P.; Sanosaka, M.; Fukushima, T.; Takahashi, H.; Kitagawa, K.; Nagaoka, Y.; Kawahara, H.; Mizuguchi, K.; Nomura, T.; Matsuda, J.; Tabata, T.; Takemori, H. Altered Actions of Memantine and NMDA-Induced Currents in a New Grid2-Deleted Mouse Line. Genes 2014, 5, 1095-1114.
Kumagai A, Fujita A, Yokoyama T, Nonobe Y, Hasaba Y, Sasaki T, Itoh Y, Koura M, Suzuki O, Adachi S, Ryo H, Kohara A, Tripathi LP, Sanosaka M, Fukushima T, Takahashi H, Kitagawa K, Nagaoka Y, Kawahara H, Mizuguchi K, Nomura T, Matsuda J, Tabata T, Takemori H. Altered Actions of Memantine and NMDA-Induced Currents in a New Grid2-Deleted Mouse Line. Genes. 2014; 5(4):1095-1114.Chicago/Turabian Style
Kumagai, Ayako; Fujita, Akira; Yokoyama, Tomoki; Nonobe, Yuki; Hasaba, Yasuhiro; Sasaki, Tsutomu; Itoh, Yumi; Koura, Minako; Suzuki, Osamu; Adachi, Shigeki; Ryo, Haruko; Kohara, Arihiro; Tripathi, Lokesh P.; Sanosaka, Masato; Fukushima, Toshiki; Takahashi, Hiroyuki; Kitagawa, Kazuo; Nagaoka, Yasuo; Kawahara, Hidehisa; Mizuguchi, Kenji; Nomura, Taisei; Matsuda, Junichiro; Tabata, Toshihide; Takemori, Hiroshi. 2014. "Altered Actions of Memantine and NMDA-Induced Currents in a New Grid2-Deleted Mouse Line." Genes 5, no. 4: 1095-1114.