Altered Actions of Memantine and NMDA-Induced Currents in a New Grid2-Deleted Mouse Line.
Altered Actions of Memantine and NMDA-Induced Currents in a New Grid2-Deleted Mouse Line.
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DOI：
10.3390/genes5041095
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发表时间：
2014-12-11
期刊：
影响因子：
3.5
通讯作者：
Takemori H
中科院分区：
文献类型：
--
作者：
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
美金刚是N-甲基-d-天冬氨酸(NMDA)受体的非竞争性拮抗剂，是被批准用于治疗中到重度阿尔茨海默病的药物。我们鉴定了一种具有自然发生突变和表现为严重腿部抽筋的共济失调表型的小鼠品系。为了研究这些突变小鼠的表型，我们筛选了几种表型调节药物，发现美金刚(10 mg/kg)破坏了突变小鼠的平衡感。此外，突变小鼠表现出减弱的视动反应(OKR)和受损的OKR学习，这在用美金刚治疗的野生型小鼠中也可以观察到。微卫星分析表明，GRID2基因缺失是导致这些表型的原因。膜片钳分析显示，GRID2基因缺失小鼠培养颗粒细胞的NMDA依赖电流变化相对较小，提示GRID2对正确的NMDA受体功能是重要的。一般来说，NMDA受体在非NMDA受体激活后被激活，如AMPA受体，在GRID2突变小鼠中也会发生AMPA受体失调。事实上，AMPA治疗增强了野生型小鼠对美金刚的敏感性，这一点从平衡感和OKR损害中可见一斑。本研究探索了GRID2的新作用，并强调了美金刚在不同遗传背景下的不良影响。
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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