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（CSPGs）是脑细胞外基质（ECM）的主要成分。我们小组最近发表在《普通精神病学档案》（Archives of General Psychiatry）上的研究结果指出，精神分裂症患者的杏仁核和内嗅皮层的CSPGs存在实质性异常，但双相情感障碍患者没有。神经胶质细胞表达CSPGs的显著增加不伴有星形细胞增生，提示精神分裂症特异性的CSPG表达异常调节。神经元周围网络的同时减少，不同神经元群周围的CSPG富集的ECM聚集，表明ECM中CSPG含量发生了改变。CSPG在调节神经元迁移、稳定突触连通性、维持神经元网络、神经元微环境和体积传递等方面的功能与精神分裂症的病理生理有直接关系。这些功能，加上精神分裂症患者杏仁核和内鼻皮层CSPG变化的大小（419-1560%），表明在这种疾病的发病机制中，神经胶质- ecm -神经元相互作用的破坏起着关键作用。本研究提出的死后和体外研究的主要目的是验证精神分裂症患者调节CSPG的分子途径可能发生改变的假设，从而导致CSPG在星形胶质细胞中积累，以及CSPG在细胞外基质神经元周围聚集体中的异常表达。这些研究分为四个具体目标，旨在测试该模型的相关方面。特异性目标1将验证这样的假设，即在精神分裂症中，内侧颞叶区域cspg阳性胶质细胞的增加与星形胶质细胞相对应，正如先前的结果所表明的那样。特异性目的2将验证精神分裂症患者内侧颞叶中调节CSPG合成和分泌到ECM的分子通路被破坏的假设。特异性Aim 3将验证ECM内CSPG表达可能减少的假设，导致表达parvalbumin的神经元周围的CSPG缺乏。特异性靶靶4将采用体外培养的人星形胶质细胞，动态测试特异性靶2中研究的生长因子和分泌载体膜蛋白在人星形胶质细胞中引起CSPG积累和减少CSPG分泌到细胞外空间的潜力。在具体目标1、2和3中，将包括一组双相情感障碍患者，以测试CSPG异常是精神分裂症特有的还是代表了主要精神病的共同特征。所提出的研究的相关性在于它们有可能揭示SZ病理生理学的一个未知和独特的方面，影响已知在该疾病中起重要作用的大脑区域。我们提出细胞外基质/神经胶质异常可能是导致精神分裂症患者神经元迁移、突触连通性以及gaba能、谷氨酸能和多巴胺能神经传递紊乱的一个统一因素。

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.