Extracellular matrix abnormalities in the medial temporal lobe of subjects with s

描述（由申请人提供）：越来越多的证据表明，我们的小组和其他人表明，杏仁核和内鼻皮层在重大精神病的发病机制中起着重要作用。我们小组最近的研究结果进一步证实了精神分裂症患者内侧颞叶区域细胞外基质（ECM）分子硫酸软骨素蛋白聚糖（CSPGs）的异常。这些变化的大效应量和广泛分布表明，CSPGs可能在精神分裂症的发病机制中起着至关重要的作用，这是以前未被怀疑的。在SZ患者的杏仁核基底外侧-皮质复合体（BLC-CO）和ECx中，被紫藤凝集素（WFA）标记的神经胶质细胞数量（推测表达CSPGs）显著增加。这些变化伴随着神经元周围网（PNNs）数量的减少，CSPGs富集的ECM网状细胞周围凝聚物。本文提出的死后、基于立体学的免疫细胞化学研究就是基于这些发现。特异性目的1旨在验证以下假设：a) SZ受试者BLC-CO和ECx中表达CSPG分子组不同成员的胶质细胞数量增加；b)同一区域cspg免疫反应性pnn数量减少；c)这些变化不伴有星形胶质细胞增生；d)在双相障碍受试者中未检测到任何变化。具体目标2将提出一个假设，即与BLC-CO和ECx发生的异常相似的异常也存在于其他内侧颞叶区域，即杏仁核的中央核和内侧核、鼻周皮层、耻骨前/旁和耻骨下。来自正常对照（n=15）、SZ （n=15）和BD （n=15）受试者的组织块可用于这些研究。在精神分裂症中特异性CSPGs改变的鉴定是理解ECM分子在这种疾病发病机制中的作用的重要一步。CSPGs在发育和成人大脑中发挥着广泛的功能，包括调节神经元迁移、轴突生长、突触可塑性、谷氨酸能和gaba能传递。这些功能与精神分裂症的病理生理学有共鸣，可能是其几个关键方面的基础。cspg相关的变化发生在一组相互连接的内侧颞叶区域，这些区域被广泛认为是SZ病理生理中的核心神经回路，这增加了它们的相关性。此外，CSPG异常的疾病特异性可能是我们理解精神分裂症和双相情感障碍之间病理生理和药理学差异的关键。总之，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，涉及内侧颞叶区域ECM功能的改变，该区域已知在该疾病中起重要作用。公共卫生相关性：尽管越来越多的证据支持杏仁核和内嗅皮层参与重大精神病，但关于它们的具体病理生理学知之甚少。对这些大脑区域的研究的相关性在于它们的功能作用，将情感和认知处理联系起来，并且在最近的研究中指出了影响精神分裂症受试者杏仁核和内嗅皮层细胞外基质的实质性但意想不到的异常。拟议的研究将提供潜在的关键信息，以提高我们对这两种疾病及其药理治疗的理解。

DESCRIPTION (provided by applicant): Growing evidence from our group and others indicates that the amygdala and the entorhinal cortex play an important role in the pathogenesis of major psychoses. Adding to this evidence, recent results from our group point to abnormalities of the extracellular matrix (ECM) molecules chondroitin sulfate proteoglycans (CSPGs) in medial temporal lobe regions of subjects with schizophrenia. The large effect size and widespread distribution of these changes suggest that CSPGs may play a crucial, and previously unsuspected, role in the pathogenesis of schizophrenia. Numbers of glial cells labeled with wisteria floribunda agglutinin (WFA), putatively expressing CSPGs, were found to be markedly increased in the basolateral-cortical complex of the amygdala (BLC-CO) and in the ECx of subjects with SZ. These changes were accompanied by decreased numbers of perineuronal nets (PNNs), mesh-like pericellular condensations of ECM enriched in CSPGs. The postmortem, stereology-based, immunocytochemical investigations proposed here are based on these findings. Specific Aim 1 is designed to test the following hypotheses: a) Numbers of glial cells expressing distinct members of the CSPG group of molecules are increased in the BLC-CO and ECx of subjects with SZ; b) Numbers of CSPG-immunoreactive PNNs will be reduced in the same regions; c) These changes are not accompanied by astrogliosis; d) No changes will be detected in subjects with BD. Specific Aim 2 will address the hypothesis that abnormalities similar to those occurring in the BLC-CO and ECx are also present in other medial temporal lobe regions, i.e. the central and medial nuclei of the amygdala, perirhinal cortex, pre-/para- subiculum and subiculum. Tissue blocks from a cohort of normal control (n=15), SZ (n=15) and BD (n=15) subjects is available for these studies. The identification of the specific CSPGs altered in schizophrenia represents a fundamental step toward understanding the role of ECM molecules in the pathogenesis of this disease. CSPGs play a broad range of functions in the developing and adult brain, including regulation of neuronal migration, axonal growth, synaptic plasticity, glutamatergic and GABAergic transmission. These functions are resonant with the pathophysiology of schizophrenia and may underlie several of its critical aspects. The occurrence of CSPG-related changes in a set of interconnected medial temporal lobe regions widely thought to represent a core neural circuit in the pathophysiology of SZ adds to their relevance. Moreover, the disease-specificity of CSPG abnormalities may be key to our understanding of pathophysiological and pharmacological differences between these schizophrenia and bipolar disorder. In summary, the relevance of the proposed studies resides in their potential of uncovering an as yet unknown and distinctive aspect of the pathophysiology of SZ, involving altered ECM functions in regions of medial temporal lobe known to play an important role in this disease.PUBLIC HEALTH RELEVANCE: Despite growing evidence supporting the involvement of the amygdala and entorhinal cortex in major psychoses, very little is known with regard to their specific pathophysiology. The relevance of investigations on these brain regions resides in their functional role, linking emotional and cognitive processing, and in recent findings pointing to substantial, yet unexpected, abnormalities affecting the extracellular matrix in the amygdala and entorhinal cortex of subjects with schizophrenia. The proposed studies will provide potentially critical information needed to improve our understanding of these two disorders and their pharmacological treatment.