Cortical deficits of glutamic acid decarboxylase 67 expression in schizophrenia: clinical, protein, and cell type-specific features.
Cortical deficits of glutamic acid decarboxylase 67 expression in schizophrenia: clinical, protein, and cell type-specific features.
复制标题
DOI：
10.1176/appi.ajp.2011.11010052
复制
发表时间：
2011-09
期刊：
影响因子：
--
通讯作者：
Lewis DA
中科院分区：
文献类型：
--
作者：
Curley AA;Arion D;Volk DW;Asafu-Adjei JK;Sampson AR;Fish KN;Lewis DA
精神分裂症的认知缺陷与背外侧前额叶皮层的活动改变有关，这归因于谷氨酸脱羧酶（GAD 67）的67 kDa亚型（主要的γ-氨基丁酸（GABA）合成酶）的表达降低。然而，很少有人知道n的前额叶GAD 67 mRNA水平与疾病的严重程度，转录到蛋白质的翻译，和轴突终末的蛋白质水平，GABA的生产和功能的关键网站。定量聚合酶链反应被用来测量GAD 67 mRNA水平在死后标本的背外侧前额叶皮层的精神分裂症患者和匹配的对照受试者没有已知的精神或神经系统疾病的历史（N=42对）。在该群组的一个子集中，其中蛋白质测量的潜在混淆被控制（N=19对），使用蛋白质印迹来定量组织中GAD 67蛋白的组织水平。在这些对中的五个中，使用多标记共聚焦单荧光来定量含有小清蛋白的GABA神经元的轴突末端中的GAD 67蛋白水平，所述神经元已知在精神分裂症中具有低水平的GAD 67 mRNA。GAD 67 mRNA水平在精神分裂症患者中显著降低（降低15%），但转录水平与疾病严重程度或慢性程度的预测因子或指标无关。在精神分裂症受试者中，GAD 67蛋白水平在总灰质（10%）和小白蛋白轴突终末（49%）中显着降低。GAD 67 mRNA表达降低在精神分裂症中是常见的，这不是患有该疾病的结果，并且它导致蛋白质翻译减少，特别是在含小清蛋白的神经元的轴突末端中，这一发现支持以下假设：小清蛋白神经元中GABA合成降低有助于精神分裂症中的背外侧前额叶皮质功能障碍和认知受损。
Cognitive deficits in schizophrenia are associated with altered activity of the dorsolateral prefrontal cortex, which has been attributed to lower expression of the 67 kDa isoform of glutamic acid decarboxylase (GAD67), the major γ-aminobutyric acid (GABA)-synthesizing enzyme. However, little is know n about the relationship of prefrontal GAD67 m RNA levels and illness severity, translation of the transcript into protein, and protein levels in axon terminals, the key site of GABA production and function. Quantitative polymerase chain reaction was used to measure GAD67 m RNA levels in postmortem specimens of dorsolateral prefrontal cortex from subjects with schizophrenia and matched comparison subjects with no know n history of psychiatric or neurological disorders (N=42 pairs). In a subset of this cohort in which potential confounds of protein measures were controlled (N=19 pairs), Western blotting was used to quantify tissue levels of GAD67 protein in tissue. In five of these pairs, multilabel confocalimm unofluorescence was used to quantify GAD67 protein levels in the axon terminals of parvalbumin-containing GABA neurons, which are know n to have low levels of GAD67 m RNA in schizophrenia. GAD67 m RNA levels were significantly lower in schizophrenia subjects (by 15%), but transcript levels were not associated with predictors or measures of illness severity or chronicity. In schizophrenia subjects, GAD67 protein levels were significantly lower in total gray matter (by 10%) and in parvalbumin axon terminals (by 49%). The findings that lower GAD67 m RNA expression is com m on in schizophrenia, that it is not a consequence of having the illness, and that it leads to less translation of the protein, especially in the axon terminals of parvalbumin-containing neurons, support the hypothesis that lower GABA synthesis in parvalbumin neurons contributes to dorsolateral prefrontal cortex dysfunction and impaired cognition in schizophrenia.
登录
查看更多内容
影响因子：
14.9
作者：
Imbeaud S;Graudens E;Boulanger V;Barlet X;Zaborski P;Eveno E;Mueller O;Schroeder A;Auffray C
通讯作者：
Auffray C
影响因子：
--
作者：
Minzenberg, Michael J.;Laird, Angela R.;Thelen, Sarah;Carter, Cameron S.;Glahn, David C.
通讯作者：
Glahn, David C.
影响因子：
2.8
作者：
Benes, FM;Todtenkopf, MS;Williams, M
通讯作者：
Williams, M
影响因子：
5.3
作者：
Hashimoto, T;Bergen, SE;Lewis, DA
通讯作者：
Lewis, DA
DOI：
10.1073/pnas.0609440103
发表时间：
2006-12-26
影响因子：
11.1
作者：
Cho, R. Y.;Konecky, R. O.;Carter, C. S.
通讯作者：
Carter, C. S.