Disruption of Extracellular Matrix-Glial Interactions in Schizophrenia

描述(申请人提供)：硫酸软骨素蛋白多糖(CSPGs)是脑细胞外基质(ECM)的主要成分。我们小组的发现，最近发表在《普通精神病学档案》上，指出了精神分裂症患者杏仁核和内嗅皮层CSPG的实质性异常，但不是双相情感障碍。胶质细胞表达CSPG的显著增加并不伴随星形细胞增多，提示精神分裂症特异性的CSPG表达的异常调节。周围神经网的同时减少，CSPG丰富的ECM聚集体围绕着不同的神经元群体，指向ECM中CSPG含量的改变。CSPG功能，如调节神经元迁移、稳定突触连接、维持神经元网络、神经元微环境和容量传递等，与精神分裂症的病理生理学有直接关系。这些功能，加上精神分裂症受试者杏仁核和内嗅觉皮质中CSPG的变化幅度(419-1560%)，表明神经胶质-细胞外基质-神经元相互作用的中断在本病的发病机制中起着关键作用。本文提出的尸检和体外研究的主要目的是验证这一假说，即精神分裂症患者调节CSPG的分子通路可能发生改变，导致CSPG在星形胶质细胞中积聚，并在细胞外基质神经节周围聚集物中异常表达。这些研究被组织成四个特定的目标，旨在测试这一模型的相关方面。《特定目标1》将验证这一假设，即在精神分裂症患者中，内侧颞叶区域CSPG阳性的神经胶质细胞与星形胶质细胞相对应，正如先前的结果所表明的那样。《特定目标2》将验证这样一种假设：在精神分裂症受试者的内侧颞叶，调节CSPG合成和分泌到ECM的分子通路被破坏。具体目标3将测试这一假设，即CSPG在ECM中的表达可能会减少，导致CSPG-贫乏的神经周网络包围着表达小白蛋白的神经元。体外对培养的人星形胶质细胞的操作将用于特定目的4，以动态地检测生长因子和分泌载体膜蛋白的潜力，在特定目的2中进行研究，以导致CSPG在人星形胶质细胞内积聚，并减少CSPG分泌到细胞外空间。在具体的目标1、2和3中，将包括一组患有双相情感障碍的受试者，以测试CSPG异常是精神分裂症特有的，还是代表主要精神病的共同特征。拟议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，影响已知在这种疾病中发挥重要作用的大脑区域。我们提出，细胞外基质/胶质细胞异常可能是导致精神分裂症神经元迁移、突触连接、GABA能、谷氨酸和多巴胺能神经传递障碍的统一因素。

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.