GABA transporter-1 deficiency confers schizophrenia-like behavioral phenotypes.
GABA transporter-1 deficiency confers schizophrenia-like behavioral phenotypes.
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GABA 转运蛋白 1 缺乏导致精神分裂症样行为表型
DOI：
10.1371/journal.pone.0069883
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Xu TL
中科院分区：
文献类型：
--
作者：
Yu Z;Fang Q;Xiao X;Wang YZ;Cai YQ;Cao H;Hu G;Chen Z;Fei J;Gong N;Xu TL
精神分裂症发病机制尚不清楚。超多巴胺和低nmda受体假说是最持久的观点。最近，新出现的证据表明精神分裂症患者的主要抑制系统gaba能神经传递发生了改变。然而，gaba能系统在精神分裂症中的病理生理作用尚不明确。在本研究中，我们利用GABA转运蛋白1 （GAT1）敲除（KO）小鼠这一独特的环境GABA升高的动物模型来研究精神分裂症相关的行为异常。我们发现GAT1 KO小鼠表现出与精神分裂症阳性、阴性和认知症状相关的多种行为异常。此外，GAT1缺乏并未改变纹状体多巴胺水平，但显著增强了前额皮质的强直性GABA电流。GABAA受体拮抗剂微螺毒素能有效改善GAT1 KO小鼠的几种行为缺陷。这些结果确定了GAT1的新功能，并表明环境中GABA的升高在精神分裂症的发病机制中起关键作用。此外，几种常用的抗精神病药物可有效治疗GAT1 KO小鼠的运动亢进，提示GAT1 KO小鼠可作为研究精神分裂症发病机制和开发新的抗精神病药物的替代动物模型。
The mechanism underlying the pathogenesis of schizophrenia remains poorly understood. The hyper-dopamine and hypo-NMDA receptor hypotheses have been the most enduring ideas. Recently, emerging evidence implicates alterations of the major inhibitory system, GABAergic neurotransmission in the schizophrenic patients. However, the pathophysiological role of GABAergic system in schizophrenia still remains dubious. In this study, we took advantage of GABA transporter 1 (GAT1) knockout (KO) mouse, a unique animal model with elevated ambient GABA, to study the schizophrenia-related behavioral abnormalities. We found that GAT1 KO mice displayed multiple behavioral abnormalities related to schizophrenic positive, negative and cognitive symptoms. Moreover, GAT1 deficiency did not change the striatal dopamine levels, but significantly enhanced the tonic GABA currents in prefrontal cortex. The GABAA receptor antagonist picrotoxin could effectively ameliorate several behavioral defects of GAT1 KO mice. These results identified a novel function of GAT1, and indicated that the elevated ambient GABA contributed critically to the pathogenesis of schizophrenia. Furthermore, several commonly used antipsychotic drugs were effective in treating the locomotor hyperactivity in GAT1 KO mice, suggesting the utility of GAT1 KO mice as an alternative animal model for studying schizophrenia pathogenesis and developing new antipsychotic drugs.
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影响因子：
82.9
作者：
Cope, David W.;Di Giovanni, Giuseppe;Fyson, Sarah J.;Orban, Gergely;Errington, Adam C.;Lorincz, Magor L.;Gould, Timothy M.;Carter, David A.;Crunelli, Vincenzo
通讯作者：
Crunelli, Vincenzo
DOI：
10.1176/appi.ajp.2009.08091445
发表时间：
2009-07
期刊：
The American journal of psychiatry
影响因子：
--
作者：
Ghose S;Gleason KA;Potts BW;Lewis-Amezcua K;Tamminga CA
通讯作者：
Tamminga CA
影响因子：
56.9
作者：
GUASTELLA, J;NELSON, N;KANNER, BI
通讯作者：
KANNER, BI
影响因子：
3.7
作者：
Errington AC;Gibson KM;Crunelli V;Cope DW
通讯作者：
Cope DW
影响因子：
4.2
作者：
Cai, You-Qing;Cai, Guo-Qiang;Fei, Jian
通讯作者：
Fei, Jian