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，仍有大约三分之一的精神分裂症患者持续出现阳性症状。最近，出现了一些治疗精神分裂症的新策略，包括谷氨酸受体的调节，这一方法部分是基于从死后、影像学和临床前研究中积累的谷氨酸传递改变的证据而开发的。虽然最初的精神分裂症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发现谷氨酸能分子表达的变化可能被概念化为谷氨酸突触重构的功能改变，继发于慢性严重精神疾病的潜在病理生理和终生使用精神药物治疗。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，这表明谷氨酸突触在谷氨酸再摄取能力方面有改变。由于谷氨酸转运体通过限制谷氨酸向相邻突触的溢出来促进兴奋性神经传递，我们假设精神分裂症患者前额叶皮质（PFC）中兴奋性氨基酸转运体（EAATs）的定位发生了改变，并可能导致这种疾病的精神病理。具体来说，我们假设具有非对称突触的EAATs的突触周围定位在精神分裂症中减少，而非对称突触是兴奋性谷氨酸传递的特征。为了验证这一假设，我们将利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外侧前额叶皮层和前扣带皮层的中间层，这些区域具有密集的互反丘脑神经支配，与这种疾病的病理生理有关。这些研究将把精神分裂症患者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改变联系起来。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谷氨酸转运体超微结构定位的影响。这些啮齿动物研究将为慢性抗精神病药物治疗对兴奋性突触组成的影响提供新的数据，并补充我们对死后发现的解释，因为大多数受试者都接受了抗精神病药物治疗。在这组实验的结论中，我们将验证这样的假设，即在精神分裂症中，具有不对称突触的谷氨酸转运体的突触周围定位减少，表明谷氨酸的突触周围再摄取减少，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，并为这种经常毁灭性疾病的诊断和治疗提供新的基础。

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.