Abnormalities of glutamate transporter localization in schizophrenia

描述(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，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，治疗精神分裂症的新策略已经出现，包括调节谷氨酸受体，这一方法在一定程度上是基于越来越多的证据，从尸检、成像和临床前研究中发现谷氨酸传递的变化。虽然精神分裂症最初的谷氨酸假说集中在NMDA受体功能障碍上，但这个假说已经扩展到包括其他谷氨酸受体、转运体和参与谷氨酸传递的酶。精神分裂症患者死后谷氨酸分子表达的变化可能被认为是重塑的谷氨酸突触的功能改变，仅次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胶质谷氨酸转运体的表达减少，这表明谷氨酸突触的重新摄取谷氨酸的能力发生了变化。由于谷氨酸转运体通过限制谷氨酸溢出到相邻突触来促进兴奋性神经传递，我们推测兴奋性氨基酸转运体(EAATs)在精神分裂症的前额叶皮质(PFC)的定位发生了改变，可能与精神分裂症的精神病理有关。具体地说，我们假设精神分裂症患者具有不对称突触的EAAT的突触周围定位减少，这是兴奋性谷氨酸传递的特征。为了评估这一假说，我们将使用电子显微镜评估精神分裂症患者死后组织中EAAT亚型的超微结构定位。我们的研究将集中在背侧外侧前额叶和前扣带回皮质的中间层，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患者前额叶皮质基因表达的变化与谷氨酸突触成分和功能的回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中谷氨酸转运体超微结构定位的影响。这些啮齿动物研究将提供关于慢性抗精神病药物治疗对兴奋性突触组成的影响的新数据，并称赞我们对尸检结果的解释，因为这些受试者中的大多数都接受了抗精神病药物治疗。在这组实验的结论中，我们将检验这一假设，即精神分裂症患者具有不对称突触的谷氨酸转运体在突触周围的定位减少，这表明突触周围对谷氨酸的重新摄取减少，谷氨酸溢出增加。这些研究将把精神分裂症的谷氨酸假说扩展到NMDA受体之外，并为这种往往具有破坏性的疾病的诊断和治疗提供新的底物。 公共卫生相关性：该项目将确定有助于精神分裂症病理生理学的大脑功能的关键要素。精神分裂症潜在分子成分的识别将为治疗这种疾病的药物开发提供新的靶点。

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.