Reelin and GAD67 Downregulation

Reelin 和 GAD67 下调

• 批准号: 6639207
• 负责人: ERMINIO COSTA
• 金额: $ 27.28万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6639207
• 关键词: cerebellum; cerebral cortex; enzyme activity; extracellular matrix proteins; gene expression; gene targeting; genetically modified animals; glutamate decarboxylase; glycoproteins; human tissue; integrins; laboratory mouse; neural cell adhesion molecules; neuroanatomy; neurogenetics; polymerase chain reaction; postmortem; psychosis; schizophrenia

DESCRIPTION: (provided by applicant) Reelin (Rein) is a glycoprotein, which in adult neocortex is preferentially fotmed and secreted y y-aminobutyric acid (GABA) secreting horizontal and double-bouquet intemeurons of layers I/il, and is mainly located in the extracellular matrix (ECM) surrounding apical dendrites and spines of cortical pyramidal neurons (layers ffl-V). The expression of Rein and glutamic acid decarboxylase 67 (GAD67), but not the disabled-I -gene product (DAB 1), are downregulated in schizophrenia postmortem brains (Appendix X). To verify whether other psychiatric disorders express similar deficits, we analyzed, blind, a new cohort of 60 postmortem brains including equal numbers of patients matched for schizophrenia (S), unipolar depression without psychosis (UD). and bipolar disorders with (BDP) or without (BD) psychosis with nonpsychiatric subjects (NP). The number of Rein-positive cells in the prefrontal cortex (PFC) as well as Rein and GAD67 mRNAs and proteins were decreased by 30 to 50 percent in S and BDP patients but not in UD when compared with NP. Group differences were absent for DAB1, GAD65 and neuronal-specific enolase (NSE) expressions, implying that no decrease of neuronal expression or damage occurred. Rein and GAD67 downregulation were unrelated to postmortem interval, pH, dose, duration, or presence of antipsychotics. In heterozygous reeler+/- mice, we found a downregulation of Rein and GAD67 mRNA expression and of dendritic spine density in pyramidal neurons of layer III. The expressions of GAD67 and Rein mRNAs were correlated in the PFC of NP and UD, and wild-type mouse frontal cortex but not S, BDP, or heterozygous RELN+/-. HYPOTHESIS: When a psychiatric disorder includes a psychotic component, the correlation between Rein and GAD67 mRNA expression existing in nonpsychotic and nonpsychiatric patients failed to be expressed. This hypothesis will be addressed with four aims: 1) to study the expression of GAD67, Reln, NSE. DAB 1. GAD65, and neuronal-specific a integrin subunit mRNAs and their correlations in other cortical areas of the above-mentioned diagnostic cohorts; 2) to study the parameters mentioned in Aim lin other diagnostic cohorts, including S, UDP, and BD patients and NP subjects in 5 cortical areas and cerebellum; 3) to study the Rein and GAD67 mRNAs and Rein-positive neuron expression in the frontal, temporal, cingulate, and visual cortex of 3 nonhuman primates, and to determine subcellular location of Rein and verify its colocation with a3 integnn receptor subunits; and 4) to study mechanistically in heterozygous Reln+/- and the GAD67 KO (GAD67+/-) whether GAD67 and Rein mRNA downregulations are a cause of dendritic spine density downregulation.

描述：(申请人提供)Reelin(Rein)是一种糖蛋白，在 成体新皮质优先培养和分泌y-氨基丁酸 (GABA)分泌第i/il层的水平和双束内神经元，以及 主要位于根尖周围的细胞外基质(ECM)中 皮质锥体神经元的树突和棘突(Ffl-V层)。这个 Rein和谷氨酸的表达 脱羧酶67(GAD67)，但不是I基因失活产物(DAB 1) 在精神分裂症死后脑中表达下调(附录X)。要验证 我们分析了其他精神疾病是否表现出类似的缺陷， 盲人，一个新的60人死后大脑队列，包括相同数量的患者 匹配精神分裂症(S)、单相抑郁无精神病(UD)。和 伴(BDP)或不伴(BD)精神病伴非精神病型的双相情感障碍 被试(NP)。前额叶皮质内Rein阳性细胞的数量 以及Rein和GAD67mRNAs和蛋白质减少了30%到50% 与NP组比较，UD组与NP组无显著差异。群体差异 DAB1、GAD65和神经元特异性烯醇化酶(NSE)表达缺失， 这意味着神经元的表达或损伤没有减少。缰绳和 GAD67表达下调与死后时间、pH、剂量、持续时间、 或有抗精神病药物的存在。在杂合的Reeler+/-小鼠中，我们发现了一个 Rein和GAD67基因表达下调及树突棘密度降低 在第三层锥体神经元中，GAD67和Rein的mRNAs表达分别为 在NP和UD以及野生型小鼠额叶皮质的PFC中相关，但不相关 S，BDP，或杂合子RELN+/-。假设：当一种精神障碍 包括一个精神成分，Rein和GAD67基因的相关性 在非精神病和非精神病患者中存在的表达失败 表达。这一假说将有四个目的：1)研究 GAD67、Reln、NSE的表达。DAB 1、GAD65和神经元特异性a整合素 大脑皮质其他区域的亚单位mRNAs及其相互关系 上述诊断队列；2)研究AIM中提到的参数 在其他诊断队列中，包括S、UDP、BD患者和NP受试者 在5个皮质区域和小脑；3)研究Rein和GAD67mRNA和 REIN阳性神经元在额叶、颞叶、扣带回和视觉中的表达 3种非人灵长类动物的大脑皮质，并确定Rein的亚细胞位置 并验证其与A3整合素受体亚基的同位；4)研究 在力学上杂合的Reln+/-和GAD67 KO(GAD67+/-)是否 GAD67和Rein基因表达下调是树突棘密度的原因 降低监管。