Extracellular anomalies in Schizophrenia: from molecules to symptoms

描述（由申请人提供）：我们小组最近的研究结果表明，精神分裂症患者的内侧颞区存在影响细胞外基质（ECM）的实质性异常，但双相情感障碍患者没有。我们的数据表明，胶质细胞和ECM中异常表达硫酸软骨素蛋白聚糖（CSPGs），这是ECM的主要成分。CSPG在发育和成长期的功能，如调节神经元迁移、轴突生长、突触连通性的稳定、神经元网络和神经元微环境的维持，与精神分裂症的病理生理直接相关。初步结果表明，SZ患者的嗅上皮（OE）和嗅球（OB）以及周围的皮肤成纤维细胞也出现了类似的异常。研究嗅觉系统（OE和OB）的ECM异常，提供了令人信服的优势。首先，神经发育功能，如神经元分化、OE的迁移和轴突向OB的生长，与成人神经功能一起贯穿一生，这使得嗅觉系统非常适合CSPGs的研究。其次，越来越多的证据表明SZ的嗅觉缺陷，特别是与阴性症状相关的嗅觉缺陷，使得嗅觉系统的研究与该疾病的临床表现直接相关。第三，OE是唯一易于活检的中枢神经系统结构，可以从中培养细胞。这些研究的主要目的是探讨精神分裂症患者CSPG异常的病理生理与该病临床表现之间的关系。CSPG异常作为一种具有精神分裂症病理生理学相关性和特异性的生物学标志物的潜力，将在ECM异常机制及其与该疾病核心症状的关联的特定假设的背景下进行评估。所检验的主要假设是，由于调节CSPG合成和分泌的分子通路被破坏，ECM异常影响SZ受试者的嗅觉系统，并且可以在周围检测到。我们假设这种异常可能与特定的嗅觉缺陷和阴性症状有关。为了验证这一假设，将在OE和皮肤成纤维细胞（活检/体外）以及OB（死后）中评估CSPG异常，这两个队列是正常对照，SZ和BD受试者。分别从皮肤和OE活检中获得的人成纤维细胞和OE原代培养物将用于体外测试对调节CSPG表达的分子机制的诊断作用。活体组织捐献者将接受嗅觉功能和精神评估量表的测试。将纳入双相障碍受试者，以测试CSPG异常是SZ特有的还是代表主要精神病的共同特征。

DESCRIPTION (provided by applicant): Recent findings from our group point to substantial abnormalities affecting the extracellular matrix (ECM) in medial temporal regions of subjects with schizophrenia, but not bipolar disorder. Our data points to anomalous expression of chondroitin sulfate proteoglycans (CSPGs), a main component of the ECM, in glial cells and ECM. CSPG functions during development and adulthod, such as regulation of neuronal migration, axon outgrowth, stabilization of synaptic connectivity, maintenance of neuronal networks and neuronal microenvironment, bear direct relevance to the pathophysiology of schizophrenia. Preliminary results suggest that similar abnormalities occur in the olfactory epithelium (OE) and olfactory bulb (OB), as well as peripherally in skin fibroblasts, of subjects with SZ. Investigations on ECM abnormalities in the olfactory system (OE and OB), as proposed here, offer compelling advantages. First, neurodevelopmental functions such as neuron diferentiation, migration in OE, and axon outgrowth toward OB, occur throughout life, alongside adult neural functions, making the olfactory system ideally suited for investigations on CSPGs. Second, growing evidence for olfactory deficits in SZ, particularly in association with negative symptoms, renders investigations on the olfactory system directly relevant to the clinical manifestations of this disease. Third, the OE is the only central nervous system structure easily accessible by biopsy, from which cel cultures can be developed. The main goal of these studies is to investigate the relationship between the pathophysiology of CSPG abnormalities in schizophrenia and clinical manifestations of this disease. The potential for CSPG abnormalities to represent a biological marker with pathophysiological relevance and specificity for schizophrenia will be assessed in the context of specific hypotheses on the mechanisms of ECM abnormalities and their association with core symptoms of this disease. The main hypothesis tested is that ECM abnormalities, due to a disruption of molecular pathways regulating CSPG synthesis and secreti0n, affect the olfactory system in subjects with SZ and can be detected peripherally. We postulate that such abnormalities may be associated with specific olfactory deficits and negative symptoms. To test this hypothesis, CSPG abnormalities will be assessed in OE and skin fibroblasts (biopsy/in vitro), as well as the OB (postmortem), from two cohorts of normal control, SZ and BD subjects. Human fibroblast and OE primary cultures obtained from skin and OE biopsies, respectively, will be used to test, in vitro, diagnosis effects on the molecular mechanisms regulating CSPG expression. Biopsy donors will be tested for olfactory functions and on psychiatric rating scales. BD subjects will be included to test whether CSPG abnormalities are specific to SZ or represent a shared feature among major psychoses.