Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder -: A postmortem brain study
Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder -: A postmortem brain study
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DOI：
10.1001/archpsyc.57.11.1061
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发表时间：
2000-11-01
影响因子：
--
通讯作者：
Costa, E
中科院分区：
文献类型：
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作者：
Guidotti, A;Auta, J;Costa, E
背景资料：卷轴素（Reelin，GABA）是一种优先由皮质γ-氨基丁酸能（GABA能）中间神经元（I层和II层）分泌的糖蛋白，其结合位于锥体神经元的树突棘上或表达失能-1基因产物（DAB 1）的III至V层GABA能中间神经元上的整联蛋白受体，所述失能-1基因产物（DAB 1）是介导GABA作用的胞质衔接蛋白。为了重复早期的研究结果，即在精神分裂症患者的大脑中，谷氨酸脱羧酶（GAD）（67），而不是DAB 1表达下调，并验证其他精神疾病是否表达类似的缺陷，我们分析了60个死后大脑的一个全新队列，包括相同数量的精神分裂症，单相抑郁症和双相情感障碍与非精神病受试者相匹配的患者。Reelin、GAD（65）、GAD（67）、DAB 1和神经元特异性烯醇化酶信使RNA（mRNA）和相应的蛋白质用定量逆转录酶-聚合酶链反应（RT-PCR）或Western印迹分析进行测定。结果：与非精神病患者相比，精神分裂症或双相情感障碍伴精神病患者的前额叶皮层和小脑中GAD（67）蛋白和mRNA的表达，以及前额叶皮层GAD（67）阳性细胞的表达均显著降低30%~ 50%，但在无精神病的单相抑郁症患者中无显著性差异。DAB 1、GAD（65）和神经元特异性烯醇化酶的表达不存在组间差异，这意味着JNN和GAD（67）下调与神经元损伤无关。Reelin和GAD（67）与死亡时间、剂量、持续时间和是否服用抗精神病药物无关。结论：精神分裂症和双相情感障碍患者前额叶皮层中的GADN和GAD（67）选择性下调，与这些参数是精神病易感因素的假设一致;这加上非精神病受试者中存在的这两个参数之间的相关性的丧失支持了这些变化可能是精神病潜在的易患因素的假设。
Background: Reelin (RELN) is a glycoprotein secreted preferentially by cortical gamma -aminobutyric acidergic (GABAergic) interneurons (layers I and II) that binds to integrin receptors located on dendritic spines of pyramidal neurons or on GABAergic interneurons of layers III through V expressing the disabled-1 gene product (DAB1), a cytosolic adaptor protein that mediates RELN action. To replicate earlier findings that RELN and glutamic acid decarboxylase (GAD)(67), but not DAB1 expression, are down-regulated in schizophrenic brains, and to verify whether other psychiatric disorders express similar deficits, we analyzed, blind, an entirely new cohort of 60 postmortem brains, including equal numbers of patients matched for schizophrenia, unipolar depression, and bipolar disorder with nonpsychiatric subjects.Methods: Reelin, GAD(65), GAD(67), DAB1, and neuron-specific-enolase messenger RNAs (mRNAs) and respective proteins were measured with quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) or Western blot analyses. Reelin-positive neurons were identified by immunohistochemistry using a monoclonal antibody.Results: Prefrontal cortex and cerebellar expression of RELN mRNA, GAD(67) protein and mRNA, and prefrontal cortex RELN-positive cells was significantly decreased by 30% to 50% in patients with schizophrenia or bipolar disorder with psychosis, but not in those with unipolar depression without psychosis when compared with nonpsychiatric subjects. Group differences were absent for DAB1,GAD(65) and neuron-specific-enolase expression implying that RELN and GAD(67) down-regulations were unrelated to neuronal damage. Reelin and GAD(67) were also unrelated to postmortem intervals, dose, duration, or presence of antipsychotic medication.Conclusions: The selective down-regulation of RELN and GAD(67) in prefrontal cortex of patients with schizophrenia and bipolar disorder who have psychosis is consistent with the hypothesis that these parameters are vulnerability factors in psychosis; this plus the loss of the correlation between these 2 parameters that exists in nonpsychotic subjects support the hypothesis that these changes may be liability factors underlying psychosis.