Assessment of glutamate transporter GLAST (EAAT1)-deficient mice for phenotypes relevant to the negative and executive/cognitive symptoms of schizophrenia.
Assessment of glutamate transporter GLAST (EAAT1)-deficient mice for phenotypes relevant to the negative and executive/cognitive symptoms of schizophrenia.
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评估谷氨酸转运蛋白 GLAST (EAAT1) 缺陷小鼠与精神分裂症的阴性和执行/认知症状相关的表型。
DOI：
10.1038/npp.2008.215
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发表时间：
2009-05
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
谷氨酸能功能障碍越来越多地与精神分裂症的病理生理学有关。目前的模型假设谷氨酸及其受体的功能障碍是这种疾病的许多症状的基础。然而，所涉及的机制并不清楚。虽然阐明谷氨酸转运体在疾病中的作用受到缺乏选择性靶向转运体的药理学工具的限制，但我们最近表明，神经胶质谷氨酸和天冬氨酸转运体在疾病中的作用是非常重要的。（玻璃;兴奋性氨基酸转运蛋白1）突变小鼠在被认为模拟精神分裂症阳性症状的行为测量上表现出异常，其中一些通过用氟哌啶醇或mGlu 2/3激动剂LY 379268治疗得以挽救。为了进一步确定GLAST在精神分裂症相关行为中的作用，我们对GLAST突变小鼠进行了一系列与精神分裂症的负面（社交退缩，快感缺乏），感觉运动门控（惊吓的前脉冲抑制）和执行/认知（辨别学习，消退）症状相关的行为范式测试。GLAST基因敲除（KO）小鼠表现出不良的筑巢行为和异常的社会性，而KO和杂合子（HET）都表现出较低的偏好，一种新的社会刺激相比，野生型同窝对照。GLAST KO，而不是HET，有一个显着减少的声音惊吓反应，但没有显着的缺陷，在惊吓的前脉冲抑制。GLAST KO和HET表现出正常的蔗糖偏好。在工具性视觉辨别任务中，KO表现出学习障碍。相比之下，简单的仪器反应的获得和消失是正常的。mGlu 2/3激动剂LY 379268未能挽救KO小鼠中的辨别障碍。这些研究结果表明，GLAST基因缺失产生选择表型异常相关的阴性和认知症状的精神分裂症。
Glutamatergic dysfunction is increasingly implicated in the pathophysiology of schizophrenia. Current models postulate that dysfunction of glutamate and its receptors underlie many of the symptoms in this disease. However, the mechanisms involved are not well understood. Although elucidating the role for glutamate transporters in the disease has been limited by the absence of pharmacological tools that selectively target the transporter, we recently showed that glial glutamate and aspartate transporter (GLAST; excitatory amino-acid transporter 1) mutant mice exhibit abnormalities on behavioral measures thought to model the positive symptoms of schizophrenia, some of which were rescued by treatment with either haloperidol or the mGlu2/3 agonist, LY379268 the mGlu2/3 agonist, LY379268. To further determine the role of GLAST in schizophrenia-related behaviors we tested GLAST mutant mice on a series of behavioral paradigms associated with the negative (social withdrawal, anhedonia), sensorimotor gating (prepulse inhibition of startle), and executive/cognitive (discrimination learning, extinction) symptoms of schizophrenia. GLAST knockout (KO) mice showed poor nesting behavior and abnormal sociability, whereas KO and heterozygous (HET) both demonstrated lesser preference for a novel social stimulus compared to wild-type littermate controls. GLAST KO, but not HET, had a significantly reduced acoustic startle response, but no significant deficit in prepulse inhibition of startle. GLAST KO and HET showed normal sucrose preference. In an instrumental visual discrimination task, KO showed impaired learning. By contrast, acquisition and extinction of a simple instrumental response was normal. The mGlu2/3 agonist, LY379268, failed to rescue the discrimination impairment in KO mice. These findings demonstrate that gene deletion of GLAST produces select phenotypic abnormalities related to the negative and cognitive symptoms of schizophrenia.
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影响因子：
10.6
作者：
Butler PD;Silverstein SM;Dakin SC
通讯作者：
Dakin SC
DOI：
10.1523/jneurosci.4904-07.2008
发表时间：
2008-08-06
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Hefner K;Whittle N;Juhasz J;Norcross M;Karlsson RM;Saksida LM;Bussey TJ;Singewald N;Holmes A
通讯作者：
Holmes A
影响因子：
15.9
作者：
Harada, Takayuki;Harada, Chikako;Tanaka, Kohichi
通讯作者：
Tanaka, Kohichi
DOI：
10.1073/pnas.0308455101
发表时间：
2004-06-01
影响因子：
11.1
作者：
Jackson, ME;Homayoun, H;Moghaddam, B
通讯作者：
Moghaddam, B
影响因子：
8.2
作者：
Holmes, Andrew
通讯作者：
Holmes, Andrew