Extracellular anomalies in Schizophrenia: from molecules to symptoms

描述(由申请人提供)：我们小组最近的发现指出，精神分裂症受试者内侧颞区细胞外基质(ECM)存在实质性异常，但双相情感障碍除外。我们的数据表明，细胞外基质的主要成分--硫酸软骨素蛋白多糖(CSPGs)在神经胶质细胞和细胞外基质中异常表达。CSPG在发育和成年期的功能，如调节神经元迁移、轴突生长、稳定突触连接、维持神经元网络和神经元微环境等，与精神分裂症的病理生理学有直接关系。初步结果表明，在SZ受试者的嗅觉上皮(OE)和嗅球(OB)以及周围皮肤成纤维细胞中也存在类似的异常。对嗅觉系统(OE和OB)细胞外基质异常的研究，提供了令人信服的优势。首先，神经发育功能，如神经元分化、在OE中的迁移和轴突向OB的生长，伴随着成人的神经功能，贯穿一生，使嗅觉系统非常适合于CSPG的研究。其次，越来越多的证据表明SZ存在嗅觉缺陷，特别是与阴性症状相关，这使得对嗅觉系统的研究与这种疾病的临床表现直接相关。第三，OE是唯一可以通过活组织检查容易获得的中枢神经系统结构，从中可以开发细胞培养。这些研究的主要目的是探讨精神分裂症患者CSPG异常的病理生理学与临床表现之间的关系。CSPG异常代表精神分裂症具有病理生理学相关性和特异性的生物标志物的可能性将在关于ECM异常的机制及其与这种疾病核心症状的关联的具体假设的背景下进行评估。检验的主要假设是，由于调节CSPG合成和分泌的分子通路中断，细胞外基质异常会影响SZ受试者的嗅觉系统，并可在外围检测到。我们推测，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，我们将评估来自两组正常对照的OE和皮肤成纤维细胞(活组织/体外)以及OB(尸检)的CSPG异常。分别从皮肤和OE活检组织中获得的人成纤维细胞和OE原代培养物将用于在体外测试对调控CSPG表达的分子机制的诊断效果。活组织检查捐赠者将接受嗅觉功能测试和精神评分。BD受试者将被包括在内，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.