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

描述(申请人提供)：来自我们小组和其他人的越来越多的证据表明，杏仁核和内嗅觉皮质在主要精神病的发病机制中发挥着重要作用。除了这一证据，我们小组最近的结果指出，精神分裂症患者内侧颞叶区域的细胞外基质(ECM)分子硫酸软骨素蛋白多糖(CSPGs)异常。这些变化的巨大效应大小和广泛分布表明，CSPG可能在精神分裂症的发病机制中发挥着关键的、以前未被怀疑的作用。紫藤凝集素(WFA)标记的胶质细胞在杏仁基底外侧皮质复合体(BLC-CO)和SZ患者的ECX中明显增加，推测表达CSPGs。伴随着这些变化的是神经周围神经网络(PNN)数量的减少，即富含CSPG的ECM的网状细胞周围凝聚。这里提出的尸检、基于体视学的免疫细胞化学研究就是基于这些发现。具体目标1旨在检验以下假设：a)SZ患者BLC-CO和ECX中表达CSPG组不同成员的胶质细胞数量增加；b)相同区域CSPG免疫阳性PNN的数量将减少；c)这些变化不伴随星形胶质细胞增生症；d)BD患者不会检测到任何变化。具体目标2将解决这样的假设，即与BLC-CO和ECX中发生的异常类似的异常也存在于其他内侧颞叶区域，即杏仁核的中央和内侧核、虹膜周围皮质、下丘前/下丘旁和下丘。来自正常对照组(n=15)、SZ(n=15)和BD(n=15)受试者的组织块可用于这些研究。识别精神分裂症中改变的特定CSPG是了解ECM分子在本病发病机制中作用的基本步骤。CSPGs在发育和成人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、谷氨酸和GABA能传递。这些功能与精神分裂症的病理生理学是一致的，并可能构成其几个关键方面的基础。与CSPG相关的改变发生在一组相互连接的内侧颞叶区域，被广泛认为是SZ病理生理学中的核心神经回路，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这些精神分裂症和双相情感障碍之间的病理生理学和药理学差异的关键。总之，拟议的研究的相关性在于他们可能揭示SZ病理生理学的一个未知和独特的方面，涉及已知在这种疾病中起重要作用的内侧颞叶区域的ECM功能改变。PUBLIC健康相关性：尽管越来越多的证据支持杏仁核和内嗅觉皮质参与主要精神疾病，但关于它们的特定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，连接情绪和认知过程，以及最近的发现，指出大量但意想不到的异常影响了精神分裂症受试者杏仁核和内嗅觉皮质的细胞外基质。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物治疗的理解。

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.