Hippocampus in Schizophrenia and Bipolar Disorder

精神分裂症和双相情感障碍中的海马体

• 批准号: 6840843
• 负责人: STEPHAN HECKERS
• 金额: $ 28.98万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6840843
• 关键词: NMDA receptors; bipolar depression; brain mapping; brain morphology; cell population study; gene expression; gene expression profiling; glutamate decarboxylase; hippocampus; histology; human tissue; immunocytochemistry; in situ hybridization; interneurons; postmortem; protein localization; proteomics; schizophrenia; somatostatin; stereotaxic techniques

This is a New Investigator proposal to study the cellular and molecular profile of the hippocampus in schizophrenia (SZ) and bipolar disorder (BD). Decreased volume of the hippocampus is one of the most consistent findings of postmortem and structural neuroimaging studies of SZ. There is emerging evidence from neuroimaging studies that the hippocampus is also smaller in BD patients, but this has not been studied yet in postmortem specimens. The cellular basis of hippocampal volume change in psychosis remains poorly understood, but it appears likely that cellular changes affect distinctsubpopulations of interneurons and that molecular changes involve genes related to GABAergic and glutamatergic neurotransmission. The applicant is proposing to study, in the same specimens, three aspects of hippocampal pathology in SZ and BD: cell number, protein expression, and gene expression. Using this integrated approach the applicant will test the hypothesis that decreased hippocampal volume in SZ and BD is regionally selective and that cellular changes are affecting subpopulations of intemeurons differentially. First, whole hippocampus preparations and stereological methods will be used to determine hippocampal volume and the total number of hippocampal neurons. We hypothesize that hippocampal changes in SZ and BD are not widespread and diffuse but selective for interneurons in the anterior region and in sectors CA2-4. Furthermore, we hypothesize that SZ is characterized by selective changes in the cell-poor layers of the hippocampus, i.e. stratum oriens and stratum radiatum/lacunosum/moleculare. Second, stereological methods and immunocytochemical markers will be employed to determine the total number of subsets of hippocampal interneurons. We hypothesize that the total number of parvalbumin-positive hippocampal interneurons will be decreased in SZ, whereas the total number of somatostatin-positive interneurons will be changed in BD. Third, in-situ hybridization experiments will test the hypothesis of a selective decrease of genes expressed in hippocampal interneurons. We hypothesize that the expression of glutamic acid decarboxylase (GAD) mRNA will be decreased in BD and that the expression of the mRNA coding for the NMDA receptor subunit 2C, localized preferentially in interneurons of the human hippocampus, is decreased in SZ. The proposed studies are designed to better understand hippocampal pathology in SZ and BD. A regionally specific volume change together with a selective dysfunction of interneurons could provide the structural basis for a role of the ..hippoc.ampus inthe cognitive deficits and clinical symptoms seen in patients with SZ and BD.

这是一个新的研究者的建议，研究海马在精神分裂症（SZ）和双相情感障碍（BD）的细胞和分子概况。海马体积减少是SZ死后和结构神经影像学研究最一致的结果之一。神经影像学研究中有新的证据表明BD患者的海马也较小，但这尚未在死后标本中进行研究。的 精神病中海马体积变化的细胞基础仍然知之甚少，但似乎细胞变化影响不同的中间神经元亚群，分子变化涉及GABA能和多巴胺能神经传递相关基因。 申请方建议在相同的标本中研究SZ和BD海马病理学的三个方面：细胞数量、蛋白表达和基因表达。使用这种综合方法，申请人将检验以下假设：SZ和BD中海马体积的减少具有区域选择性，并且细胞变化差异性地影响中间神经元的亚群。首先，将使用整个海马制备物和体视学方法来确定海马体积和海马神经元的总数。我们 假设SZ和BD的海马变化不是广泛和弥漫的，而是对前部区域和CA 2 -4区的中间神经元具有选择性。此外，我们假设，SZ的特点是选择性变化 在海马的细胞贫乏层，即定向层和放射层/腔隙层/分子层中。其次，采用体视学方法和免疫细胞化学标记物确定海马中间神经元亚群的总数。我们假设小白蛋白阳性海马中间神经元的总数 SZ中生长抑素阳性中间神经元的数量将减少，而BD中生长抑素阳性中间神经元的总数将改变。第三，原位杂交实验将测试海马中间神经元中表达的基因的选择性减少的假设。我们假设，谷氨酸脱羧酶（GAD）mRNA的表达将在BD和表达的NMDA受体亚基2C，本地化优先在人海马的中间神经元的mRNA编码减少，在SZ。 拟定的研究旨在更好地了解SZ和BD的海马病理学。区域特定体积变化以及中间神经元的选择性功能障碍可以为神经元的作用提供结构基础。在SZ和BD患者中观察到的认知缺陷和临床症状中，