GABA transporter deficiency causes tremor, ataxia, nervousness, and increased GABA-induced tonic conductance in cerebellum
GABA transporter deficiency causes tremor, ataxia, nervousness, and increased GABA-induced tonic conductance in cerebellum
复制标题
DOI：
10.1523/jneurosci.3364-04.2005
复制
发表时间：
2005-03-23
影响因子：
5.3
通讯作者：
Lester, HA
中科院分区：
文献类型：
--
作者：
Chiu, CS;Brickley, S;Lester, HA
GABA转运子亚型1（GAT 1）敲除（KO）小鼠显示正常的生殖和寿命，但具有降低的体重（雌性，-10%;雄性，-20%）和在0.2-1.5/h频率范围内的较高体温波动。小鼠GAT 1（mGAT 1）KO小鼠表现出运动障碍，包括步态异常、恒定的25 - 32 Hz震颤（氟硝西泮加重）、转棒性能降低和在饲养笼中运动活动减少。旷场测试显示，探索活动延迟，饲养减少，对中心区域的访问减少，总旅行距离没有变化。mGAT 1 KO小鼠在声惊吓反应方面没有表现出差异，但在前脉冲抑制方面表现出缺陷。这些旷场和前脉冲抑制结果表明，mGAT 1 KO小鼠表现出轻度焦虑或紧张。mGAT 1 KO小鼠中受损的GABA摄取导致小脑颗粒和浦肯野细胞中GABA（A）受体介导的紧张性传导增加。GABA从突触间隙的清除率降低可能是小脑颗粒细胞中自发IPSC衰减较慢的原因。在mGAT 1 KO小鼠中，与GABA传递相关的其他蛋白质或结构几乎没有代偿性变化，包括小脑或海马中的非GAT 1依赖性GABA摄取、GABA能中间神经元数量以及GABA（A）-、囊泡GABA转运蛋白-、GAD 65-和GAT 3-免疫反应性结构。因此，mGAT 1 KO小鼠中存在的过量细胞外GABA导致部分表型复制噻加宾临床副作用的行为，表明这些副作用是靶向广泛表达的GAT 1转运蛋白系统的治疗策略所固有的。
GABA transporter subtype 1 (GAT1) knock-out ( KO) mice display normal reproduction and life span but have reduced body weight ( female, - 10%; male, - 20%) and higher body temperature fluctuations in the 0.2-1.5/h frequency range. Mouse GAT1 (mGAT1) KO mice exhibit motor disorders, including gait abnormality, constant 25 - 32 Hz tremor, which is aggravated by flunitrazepam, reduced rotarod performance, and reduced locomotor activity in the home cage. Open-field tests show delayed exploratory activity, reduced rearing, and reduced visits to the central area, with no change in the total distance traveled. The mGAT1 KO mice display no difference in acoustic startle response but exhibit a deficiency in prepulse inhibition. These open-field and prepulse inhibition results suggest that the mGAT1 KO mice display mild anxiety or nervousness. The compromised GABA uptake in mGAT1 KO mice results in an increased GABA(A) receptor-mediated tonic conductance in both cerebellar granule and Purkinje cells. The reduced rate of GABA clearance from the synaptic cleft is probably responsible for the slower decay of spontaneous IPSCs in cerebellar granule cells. There is little or no compensatory change in other proteins or structures related to GABA transmission in the mGAT1 KO mice, including GAT1-independent GABA uptake, number of GABAergic interneurons, and GABA(A)-, vesicular GABA transporter-, GAD65-, and GAT3-immunoreactive structures in cerebellum or hippocampus. Therefore, the excessive extracellular GABA present in mGAT1 KO mice results in behaviors that partially phenocopy the clinical side effects of tiagabine, suggesting that these side effects are inherent to a therapeutic strategy that targets the widely expressed GAT1 transporter system.