Reelin and GAD67 Downregulation

Reelin 和 GAD67 下调

• 批准号: 6881176
• 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 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6881176
• 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：（由申请人提供）Reelin（Rein）是一种糖蛋白， 成年人的新皮层优先形成和分泌γ-氨基丁酸 （GABA）分泌I/II层的水平和双束中间神经元，和 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（层ffl-V）。的 Rein和谷氨酸的表达 脱羧酶67（GAD 67），而不是失活的-I-基因产物（DAB 1）， 在精神分裂症死后大脑中下调（附录X）。验证 我们分析了其他精神疾病是否表现出类似的缺陷， 一个新的队列，包括60个死后的大脑，包括相同数量的病人， 与精神分裂症（S）、无精神病的单相抑郁症（UD）匹配。和 双相情感障碍伴（BDP）或不伴（BD）精神病伴非精神病性 受试者（NP）前额叶皮层（PFC）中Rein阳性细胞的数量 以及Rein和GAD 67的mRNA和蛋白质减少了30%到50%， 与NP相比，S和BDP患者中有显著性差异，但UD患者中无显著性差异。群体差异 DAB 1、GAD 65和神经元特异性烯醇化酶（NSE）表达缺失， 这意味着没有发生神经元表达的降低或损伤。赖因和 GAD 67下调与死后间隔、pH、剂量、持续时间无关， 或服用抗精神病药物在杂合子reeler+/-小鼠中，我们发现 下调Rein和GAD 67 mRNA表达及树突棘密度 在第三层的锥体神经元。GAD 67和Rein mRNA的表达分别为： NP和UD的PFC与野生型小鼠额叶皮层相关，但不 S、BDP或杂合的BDN +/-。假设：当一种精神疾病 包括精神病成分、Rein与GAD 67 mRNA之间的相关性 在非精神病和非精神病患者中存在的表达未能被 表达。这一假设将解决与四个目标：1）研究 GAD 67、Reln、NSE的表达。DAB 1. GAD 65和神经元特异性α整合素 亚基mRNA及其在大脑皮层其他区域的相关性 上述诊断队列; 2）研究Aim中提到的参数 其他诊断队列，包括S、UDP和BD患者和NP受试者 在5个皮质区和小脑中; 3）研究Rein和GAD 67 mRNA， Rein阳性神经元在额叶、颞叶、扣带回和视觉区的表达 3个非人灵长类动物的皮质，并确定Rein的亚细胞定位 并验证其与a3 integn受体亚基的共定位;以及4）研究 在杂合子Reln+/-和GAD 67 KO（GAD 67 +/-）中， GAD 67和Rein mRNA下调是树突棘密度的原因 下调

项目成果

The combination of huperzine A and imidazenil is an effective strategy to prevent diisopropyl fluorophosphate toxicity in mice.

石杉碱甲和咪达西尼的组合是预防二异丙基氟磷酸盐对小鼠毒性的有效策略。

• DOI: 10.1073/pnas.0807172105
• 发表时间: 2008
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Pibiri,Fabio;Kozikowski,AlanP;Pinna,Graziano;Auta,James;Kadriu,Bashkim;Costa,Erminio;Guidotti,Alessandro
• 通讯作者: Guidotti,Alessandro