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

患有 s 的受试者内侧颞叶的细胞外基质异常

基本信息

批准号：
7452041
负责人：
Sabina Berretta
金额：
$ 18.11万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-13 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7452041
关键词：
Address Adult Affect Agglutinins Amygdaloid structure Antibodies Astrocytes Autopsy Bipolar Disorder Brain Brain region CSPG3 gene Cell Nucleus Cells Central Medial Thalamic Nucleus Chondroitin Sulfate Proteoglycan Cognitive Complex Diagnosis Disease Emotional Extracellular Matrix Family Functional disorder Glial Fibrillary Acidic Protein Glutamates Goals Histocytochemistry Investigation Label Laboratory Finding Lateral Lectin Link Measures Medial Neuraxis Neuroglia Neurons Nuclear Numbers Pathogenesis Pharmacological Treatment Physical condensation Play Population Process Psychotic Disorders Range Regulation Relative (related person)Role Schizophrenia Specificity Synaptic plasticity Temporal Lobe Testing Thinking Tissues Wisteria Work aggrecan astrogliosis axon growth base brevican cohort density design entorhinal cortex immunoreactivity improved member migration neural circuit phosphacan selective expression size transmission process versican

项目摘要

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.

描述（由申请人提供）：我们小组和其他人的越来越多的证据表明，杏仁核和内嗅皮层在主要精神病的发病机理中起着重要作用。除此证据外，我们小组的最新结果表明细胞外基质（ECM）分子软骨素硫酸盐蛋白聚糖（CSPG）在具有精神分裂症受试者的内侧颞叶区域中。这些变化的效果大小和广泛的分布表明，CSPG在精神分裂症的发病机理中起着至关重要的，以前没有引起的作用。在杏仁核（BLC-CO）的基底外侧皮质复合物（BLC-CO）和SZ受试者的ECX中，发现用富富兰达凝集素（WFA）标记的葡萄球菌细胞数量明显增加。这些变化伴随着会周神经元网（PNN）的数量减少，富含CSPG的ECM的网状细胞细胞凝结。此处提出的后验尸，基于立体的免疫细胞化学研究是基于这些发现。特定的目标1旨在检验以下假设：a）在具有SZ的受试者的BLC-CO和ECX中增加表达CSPG分子的不同成员的神经胶质细胞数量； b）在同一地区，CSPG-免疫反应性PNN的数量将减少； c）这些变化不伴有星形胶质症； d）在患有BD的受试者中将无法检测到任何变化。 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亚致。这些研究可用于正常对照组（n = 15），SZ（n = 15）和BD（n = 15）受试者的组织块。精神分裂症中改变的特定CSPG的鉴定是了解ECM分子在该疾病发病机理中的作用的基本步骤。 CSPG在发育和成人大脑中起广泛的功能，包括调节神经元迁移，轴突生长，突触可塑性，谷氨酸能和GABA能传播。这些功能与精神分裂症的病理生理学共鸣，并可能是其几个关键方面的基础。在一组相互联系的内侧颞叶区域中，CSPG相关的变化被广泛认为代表了SZ病理生理学中的核心神经回路，这增加了其相关性。此外，CSPG异常的疾病特异性可能是我们对这些精神分裂症和双相情感障碍之间病理生理和药理差异的理解的关键。总而言之，拟议研究的相关性在于它们的潜力是发现SZ的病理生理学尚未清楚和独特的方面，涉及已知在这种疾病中起重要作用的内侧颞叶区域的ECM功能的改变。公共健康相关性：尽管越来越多的证据支持杏仁核和内嗅皮层参与主要精神病，但就其特定的病理生理学而言，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，将情绪和认知处理联系起来，并且在最近的发现中，指出了影响杏仁核和精神分裂症受试者内hin的细胞外基质的实质但出乎意料的异常。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。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Aggrecan and chondroitin-6-sulfate abnormalities in schizophrenia and bipolar disorder: a postmortem study on the amygdala.

DOI：
10.1038/tp.2014.128
发表时间：
2015-01-20
期刊：
Translational psychiatry
影响因子：
6.8
作者：
Pantazopoulos H;Markota M;Jaquet F;Ghosh D;Wallin A;Santos A;Caterson B;Berretta S
通讯作者：
Berretta S

Losing the sugar coating: potential impact of perineuronal net abnormalities on interneurons in schizophrenia.