| First Author | Kumagai A | Year | 2014 |
| Journal | Genes (Basel) | Volume | 5 |
| Issue | 4 | Pages | 1095-114 |
| PubMed ID | 25513882 | Mgi Jnum | J:271079 |
| Mgi Id | MGI:6279567 | Doi | 10.3390/genes5041095 |
| Citation | Kumagai A, et al. (2014) Altered Actions of Memantine and NMDA-Induced Currents in a New Grid2-Deleted Mouse Line. Genes (Basel) 5(4):1095-114 |
| abstractText | 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. |
