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- Title
Altered Actions of Memantine and NMDA-Induced Currents in a New Grid2-Deleted Mouse Line.
- Authors
Ayako Kumagai; Akira Fujita; Tomoki Yokoyama; Yuki Nonobe; Yasuhiro Hasaba; Tsutomu Sasaki; Yumi Itoh; Minako Koura; Osamu Suzuki; Shigeki Adachi; Haruko Ryo; Arihiro zohara; Tripathi, Lokesh P.; Masato Sanosaka; Toshiki Fukushima; Hiroyuki Takahashi; Kazuo Kitagawa; Yasuo Nagaoka; Hidehisa Kawahara; Kenji Mizuguchi
- 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.
- Subjects
MEMANTINE; METHYL aspartate receptors; MICROSATELLITE repeats; PATCH-clamp techniques (Electrophysiology); AMPA receptors; MICE
- Publication
Genes, 2014, Vol 5, Issue 4, p1095
- ISSN
2073-4425
- Publication type
Article
- DOI
10.3390/genes5041095