Excitatory Amino Acid Transporter Expression and Regulation in Schizophrenia

描述（由申请人提供）：兴奋性氨基酸转运蛋白（EAAT）是负责突触谷氨酸再摄取的分子家族。这些转运体的表达和调节促进谷氨酸从突触的清除，并在长时程增强和突触可塑性中起关键作用。有令人信服的证据表明，精神分裂症患者的谷氨酸传输皮质异常，但EAAT在精神分裂症中的确切作用仍然未知。据推测，EAAT的表达和调节在前额叶和前扣带皮层在精神分裂症中改变的模式与谷氨酸再摄取增加一致。在精神分裂症患者和对照受试者的尸检组织中，将使用激光捕获显微镜和定量PCR测量细胞水平的基因表达，将使用酶促去糖基化和蛋白质印迹分析研究翻译后修饰，并将使用免疫共沉淀测量转运蛋白和一组调节转运蛋白活性的蛋白质之间的相互作用。精神分裂症影响全球1%的人口，2002年美国的成本估计为627亿美元。这项研究将导致我们对谷氨酸再摄取如何在精神分裂症中改变的理解取得重大进展。确定特定的异常，丘脑能神经传递可能会被用来针对更有效的诊断和治疗策略。

DESCRIPTION (provided by applicant): The excitatory amino acid transporters (EAATs) are a family of molecules responsible for synaptic glutamate reuptake. Expression and regulation of these transporters facilitates clearance of glutamate from the synapse and plays a pivotal role in long-term potentiation and synaptic plasticity. Compelling evidence has implicated cortical abnormalities of glutamate transmission in schizophrenia, but the precise role of the EAATs in schizophrenia remains unknown. It is hypothesized that expression and regulation of EAATs are altered in the prefrontal and anterior cingulate cortices in schizophrenia in a pattern consistent with increased glutamate reuptake. In postmortem tissue from patients with schizophrenia and control subjects, cell level gene expression will be measured using laser capture microscopy and quantitative PCR, post translational modification will be studied using enzymatic deglycoslation and Western blot analysis, and interaction between the transporters and a set of proteins that modulate transporter activity will be measured using co-immunoprecipitation. Schizophrenia affects 1% of the population worldwide and the cost to the U.S. in 2002 was estimated to be $62.7 billion. This research will lead to significant advances in our understanding of how glutamate reuptake may be altered in schizophrenia. Defining the specific abnormalities in glutamatergic neurotransmission may be used to target more effective diagnostic and treatment strategies.