Disruption of Extracellular Matrix-Glial Interactions in Schizophrenia

描述（由申请人提供）：硫酸软骨素蛋白聚糖（CSPG）是脑细胞外基质（ECM）的主要成分。我们小组的研究结果最近发表在《普通精神病学档案》上，指出精神分裂症受试者杏仁核和内嗅皮层的CSPGs存在显著异常，但双相情感障碍受试者没有。表达CSPGs的胶质细胞的显著增加并不伴随星形胶质细胞增多，表明CSPG表达的精神分裂症特异性异常调节。同时减少神经元周围的网络，CSPG富集ECM聚集体周围不同的神经元群体，点改变CSPG含量的ECM。CSPG的功能，如调节神经元迁移，稳定突触连接，维持神经元网络，神经元微环境和体积传输，承担直接相关的精神分裂症的病理生理。这些功能，连同患有精神分裂症的受试者的杏仁核和内嗅皮层中的CSPG变化的幅度（419-1560%），指出了胶质细胞-ECM-神经元相互作用的破坏在该疾病的发病机制中的关键作用。在这里提出的尸检和体外研究的主要目标是测试的假设，即调节CSPGs的分子途径可能会改变精神分裂症，导致CSPG积累星形胶质细胞和异常CSPG表达细胞外基质神经元周围聚集体。这些研究分为四个具体目标，旨在测试这一模式的相互关联的方面。具体目标1将测试的假设，在精神分裂症，增加CSPG阳性胶质细胞在内侧颞叶区域对应于星形胶质细胞，如先前的结果所建议的。具体目标2将检验以下假设：在精神分裂症受试者的内侧颞叶中，调节CSPG合成和分泌到ECM中的分子途径被破坏。具体目标3将检验ECM内的CSPG表达可能减少的假设，导致CSPG贫乏的神经元周网围绕表达小清蛋白的神经元。将在特定目标4中使用对培养的人星形胶质细胞的体外操作，以动态检测特定目标2中研究的生长因子和分泌性载体膜蛋白引起人星形胶质细胞中CSPG蓄积和CSPG分泌至细胞外间隙减少的潜力。在具体目标1、2和3中，将纳入一组双相情感障碍受试者，以检测CSPG异常是否为精神分裂症特有或代表重度精神病的共同特征。拟议研究的相关性在于其揭示SZ病理生理学的一个未知和独特方面的潜力，影响已知在这种疾病中发挥重要作用的脑区。我们提出，细胞外基质/神经胶质异常可能是一个统一的因素，有助于神经元迁移，突触连接，GABA能，多巴胺能和多巴胺能神经传递的精神分裂症的障碍。 公共卫生相关性：拟议的研究的相关性在于他们的贡献的分子机制和细胞群参与细胞外基质异常的精神分裂症，这种疾病的病理生理学的一个新的和潜在的独特方面的理解。这种异常可能会影响广泛的发育和成人神经功能，如神经元迁移，神经传递和突触可塑性。在内侧颞叶在情绪和知觉处理中的作用的背景下，这些功能的中断可能在精神分裂症的一些主要症状的病理生理学中发挥关键作用，例如扁平情感，社交和认知障碍，妄想性思维和焦虑。

DESCRIPTION (provided by applicant): Chondroitin sulfate proteoglycans (CSPGs) are a main component of the brain extracellular matrix (ECM). Findings from our group, recently published in the Archives of General Psychiatry, point to substantial abnormalities affecting CSPGs in the amygdala and entorhinal cortex of subjects with schizophrenia, but not bipolar disorder. Marked increases of glial cells expressing CSPGs were not accompanied by astrocytosis, suggesting schizophrenia-specific anomalous regulation of CSPG expression. Concurrent reductions of perineuronal nets, CSPG-enriched ECM aggregates surrounding distinct neuronal populations, point to altered CSPG content in the ECM. CSPG functions, such as regulation of neuronal migration, stabilization of synaptic connectivity, maintenance of neuronal networks, neuronal microenvironment and volume transmission, bear direct relevance to the pathophysiology of schizophrenia. These functions, together with the magnitude of CSPG changes (419-1560%) in amygdala and entorhinal cortex of subjects with schizophrenia, point to a pivotal role for a disruption of glial-ECM-neuronal interactions in the pathogenesis of this disease. The main goal of the postmortem and in vitro studies proposed here is to test the hypothesis that molecular pathways regulating CSPGs may be altered in schizophrenia, causing CSPG accumulation in astrocytes and abnormal CSPG expression in extracellular matrix perineuronal aggregates. These studies are organized in four specific aims, designed to test interrelated aspects of this model. Specific Aim 1 will test the hypothesis that, in schizophrenia, increased CSPG-positive glial cells in medial temporal lobe regions correspond to astrocytes, as suggested by previous results. Specific Aim 2 will test the hypothesis that the molecular pathways regulating CSPG synthesis and secretion into the ECM are disrupted in the medial temporal lobe of subjects with schizophrenia. Specific Aim 3 will test the hypothesis that CSPG expression within the ECM may be reduced, resulting in CSPGs-impoverished perineuronal nets surrounding parvalbumin-expressing neurons. In vitro manipulations on cultured human astrocytes will be used in Specific Aim 4 to test dynamically the potential of growth factors and secretory carrier membrane proteins, investigated in Specific Aim 2, to cause CSPG accumulation in human astrocytes and decreased CSPG secretion into the extracellular space. In Specific Aims 1, 2 and 3, a group of subjects with bipolar disorder will be included to test whether CSPG abnormalities are specific to schizophrenia or represent a shared feature among major psychoses. The relevance of the proposed studies resides in their potential of uncovering an as yet unknown and distinctive aspect of the pathophysiology of SZ, affecting brain regions known to play an important role in this disease. We put forward that extracellular matrix/glial abnormalities may represent a unifying factor contributing to disturbances of neuronal migration, synaptic connectivity, and GABAergic, glutamatergic and dopaminergic neurotransmission in schizophrenia. PUBLIC HEALTH RELEVANCE: The relevance of the proposed studies resides in their contribution to the understanding of the molecular mechanisms and cellular populations involved in extracellular matrix abnormalities in schizophrenia, a novel and potentially distinctive aspect of the pathophysiology of this disease. Such abnormalities may affect a broad range of developmental and adult neural functions such as neuronal migration, neurotransmission and synaptic plasticity. Set in the context of the medial temporal lobe role in emotion and perceptual processing, a disruption of such functions may play a key role in the pathophysiology of some of the main symptoms of schizophrenia, such as flat affect, social and cognitive impairment, delusional thinking and anxiety.