Hippocampus in Schizophrenia and Bipolar Disorder

这是一项研究人员的新建议，旨在研究精神分裂症(SZ)和双相情感障碍(BD)患者海马区的细胞和分子特征。海马区体积缩小是SZ尸检和结构神经成像研究中最一致的发现之一。来自神经成像研究的新证据表明，BD患者的海马体也较小，但这一点尚未在尸检标本中进行研究。这个 精神病患者海马区体积变化的细胞学基础尚不清楚，但细胞变化可能影响不同的中间神经元亚群，分子变化涉及与GABA能和谷氨酸能神经传递相关的基因。 申请人建议，在相同的标本中，研究SZ和BD海马区病理的三个方面：细胞数量、蛋白质表达和基因表达。使用这种综合的方法，申请者将检验假设，即SZ和BD的海马体体积减少是局部选择性的，细胞变化正在不同地影响内神经元亚群。首先，将采用全海马区制备和体视学方法测定海马区体积和海马神经元总数。我们 假设SZ和BD的海马区变化不是广泛的和弥漫性的，而是选择性地针对前区和CA2-4区的中间神经元。此外，我们假设SZ具有选择性变化的特征 在海马区缺乏细胞的层，即东方层和放射层/腔隙/分子层。其次，将使用体视学方法和免疫细胞化学标记物来确定海马区中间神经元亚群的总数。我们假设小白蛋白阳性的海马区中间神经元总数 而生长抑素阳性中间神经元的总数在BD时发生改变。第三，原位杂交实验将检验海马区中间神经元基因表达选择性减少的假说。我们推测BD时谷氨酸脱羧酶(GAD)mRNA的表达降低，SZ时编码NMDA受体2C亚单位的mRNA表达降低，该基因主要定位于人海马神经元。 建议的研究旨在更好地了解SZ和BD的海马区病理。在SZ和BD患者的认知缺陷和临床症状中，特定区域的体积变化和中间神经元的选择性功能障碍可能为……髋臼在认知障碍和临床症状中的作用提供结构基础。

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.