Abnormalities of glutamate transporter localization in schizophrenia

描述（由申请人提供）：虽然用抗精神病药物治疗精神分裂症彻底改变了这种疾病的临床管理，但尽管进行了多次抗精神病药物试验，但大约三分之一的精神分裂症患者仍有持续的阳性症状。最近，出现了治疗精神分裂症的新策略，包括调节谷氨酸受体，这种方法的开发部分是基于尸检、成像和临床前研究中谷氨酸传输改变的大量证据。虽然精神分裂症最初的谷氨酸假说主要集中在 NMDA 受体功能障碍上，但这一假说已扩展到包括其他谷氨酸受体、转运蛋白和参与谷氨酸传输的酶。精神分裂症中谷氨酸能分子表达变化的死后发现可以被概念化为重塑的谷氨酸突触的功能改变，继发于慢性严重精神疾病的潜在病理生理学和终生精神药物治疗。我们发现在这种疾病中神经胶质谷氨酸转运蛋白的表达减少，表明谷氨酸突触的谷氨酸再摄取能力发生了改变。由于谷氨酸转运蛋白通过限制谷氨酸溢出到邻近突触来促进兴奋性神经传递，因此我们推测精神分裂症的前额皮质（PFC）中兴奋性氨基酸转运蛋白（EAAT）的定位发生了改变，并且可能有助于这种疾病的精神病理学。具体来说，我们假设具有不对称突触的 EAAT 的突触周围定位（兴奋性谷氨酸传递的特征）在精神分裂症中减少。为了评估这一假设，我们将使用电子显微镜评估精神分裂症受试者死后组织中 EAAT 亚型的超微结构定位。我们的研究将集中于背外侧前额叶和前扣带皮层的中层，这些区域具有密集的丘脑相互神经支配，与这种疾病的病理生理学有关。这些研究将把精神分裂症中 PFC 基因表达的变化与谷氨酸突触组成和功能的电路特异性变化联系起来。我们还计划评估慢性典型和非典型抗精神病药物治疗对大鼠 PFC 中谷氨酸转运蛋白超微结构定位的影响。这些啮齿动物研究将提供关于长期抗精神病药物治疗对兴奋性突触组成的影响的新数据，并补充我们对尸检结果的解释，因为大多数受试者都接受了抗精神病药物治疗。在这组实验结束时，我们将检验这样的假设：精神分裂症中具有不对称突触的谷氨酸转运蛋白的突触周围定位减少，这表明谷氨酸的突触周围再摄取减少和谷氨酸溢出增加。这些研究将精神分裂症的谷氨酸假说扩展到 NMDA 受体之外，并为诊断和治疗这种经常毁灭性的疾病提供新的底物。 公共卫生相关性：该项目将确定导致精神分裂症病理生理学的大脑功能的关键要素。鉴定精神分裂症的分子元件将为开发治疗这种疾病的药物提供新的靶点。

DESCRIPTION (provided by applicant): While the treatment of schizophrenia with antipsychotic medications revolutionized the clinical management of this illness, approximately one-third of patients with schizophrenia have persistent positive symptoms despite multiple trials of antipsychotic medicines. Recently, new strategies for the treatment of schizophrenia have emerged, including modulation of glutamate receptors, an approach which was developed, in part, based on an accumulating body of evidence of alterations in glutamate transmission from postmortem, imaging, and preclinical studies. While the initial glutamate hypothesis of schizophrenia was focused on NMDA receptor dysfunction, this hypothesis has been extended to include other glutamate receptors, transporters, and enzymes involved in glutamate transmission. Postmortem findings of changes in the expression of gluta- matergic molecules in schizophrenia may be conceptualized as functional alterations of remodeled glutamate synapses, secondary to the underlying pathophysiology of chronic severe mental illness and a lifetime of treatment with psychotropic medications. We have found decreased expression of glial glutamate transporters in this illness, suggesting that glutamate synapses have alterations in glutamate reuptake capacity. Since glutamate transporters facilitate excitatory neurotransmission by limiting glutamate spillover to adjacent synapses, we postulate that the localization of excitatory amino acid transporters (EAATs) is altered in the prefrontal cortex (PFC) in schizophrenia, and may contribute to psychopathology in this illness. Specifically, we hypothesize that perisynaptic localization of EAATs with asymmetric synapses, which are characteristic of excitatory glutamate transmission, is decreased in schizophrenia. To evaluate this hypothesis, we will assess the ultrastructural localization of EAAT isoforms using electron microscopy in postmortem tissue from subjects with schizophrenia. Our studies will focus on the middle layers of the dorsal lateral prefrontal and anterior cingulate cortices, regions with dense reciprocal thalamic innervation that are implicated in the pathophysiology of this illness. These studies will link identified changes in gene expression in the PFC in schizophrenia with circuit specific alterations in glutamate synapse composition and function. We also plan to assess the effects of chronic typical and atypical antipsychotic treatment on ultrastructural localization of glutamate transporters in the rat PFC. These rodent studies will provide novel data on the effects of chronic antipsychotic treatment on the composition of excitatory synapses, and compliment the interpretation of our postmortem findings, since most of these subjects were treated with antipsychotics. At the conclusion of this set of experiments, we will have tested the hypothesis that perisynaptic localization of glutamate transporters with asymmetric synapses is diminished in schizophrenia, suggesting decreased perisynaptic reuptake of glutamate and increased glutamate spillover. These studies will extend the glutamate hypothesis of schizophrenia beyond the NMDA receptor and provide new substrates for diagnosis and treatment of this often devastating illness. PUBLIC HEALTH RELEVANCE: This project will identify the critical elements of brain function that contribute to the pathophysiology of schizophrenia. Identification of the molecular elements underlying schizophrenia will provide new targets for the development of medicines to treat this illness.