A decrease of reelin expression as a putative vulnerability factor in schizophrenia
A decrease of reelin expression as a putative vulnerability factor in schizophrenia
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DOI：
10.1073/pnas.95.26.15718
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发表时间：
1998-12-22
影响因子：
11.1
通讯作者：
Costa, E
中科院分区：
文献类型：
--
作者：
Impagnatiello, F;Guidotti, AR;Costa, E
比较了精神分裂症患者和其匹配的非精神病受试者的死后前额叶皮质（PFC）（Brodmann区10和46），颞叶皮质（Brodmann区22），前丘，尾状核和小脑的reelin（reelin）mRNA和reelin（reelin）蛋白含量。在研究的所有脑区中，精神分裂症患者的BRN及其mRNA显著减少（约50%）;这种减少在未分化或偏执型精神分裂症患者中相似。为了排除死后mRNA降解引起的可能伪影，我们测量了来自γ-氨基丁酸（GABA）（A）受体α（1）和α（5）以及烟碱乙酰胆碱受体α（7）亚基的相同PFC提取物中的mRNA。尽管α（7）烟碱乙酰胆碱受体亚单位的表达是正常的，但当存在精神分裂症时，GABA（A）的α（1）和α（5）受体亚单位的表达增加。在PFC、颞叶皮质、海马的GABA能中间神经元和小脑的GABA能颗粒细胞中，GABA能mRNA优先表达。一种蛋白质publets作为细胞内靶点的信号转导级联反应触发释放到细胞外基质中的BFN蛋白被称为小鼠残疾-1（DAB 1），并在PFC和海马锥体神经元，小脑浦肯野神经元的神经质中以相当的水平表达精神分裂症患者和非精神病受试者;这三种类型的神经元不表达BFN蛋白。在相同的颞叶皮层样本中，我们发现，在大约50%的DAB 1蛋白表达的变化，但在JNK蛋白的减少。我们还观察到GAD 67的大幅度（高达70%）降低，但GAD 65蛋白含量仅小幅降低。这些发现被解释为精神分裂症的病因学的神经发育/脆弱性“两击”模型。
Postmortem prefrontal cortices (PFC) (Brodmann's areas 10 and 46), temporal cortices (Brodmann's area 22), hippocampi, caudate nuclei, and cerebella of schizophrenia patients and their matched nonpsychiatric subjects were compared for reelin (RELN) mRNA and reelin (RELN) protein content. In all of the brain areas studied, RELN and its mRNA were significantly reduced ( approximate to 50%) in patients with schizophrenia; this decrease was similar in patients affected by undifferentiated or paranoid schizophrenia. To exclude possible artifacts caused by postmortem mRNA degradation, we measured the mRNAs in the same PFC extracts from gamma-aminobutyric acid (GABA)(A) receptors alpha(1) and alpha(5) and nicotinic acetylcholine receptor alpha(7) subunits. Whereas the expression of the alpha(7) nicotinic acetylcholine receptor subunit was normal, that of the alpha(1) and alpha(5) receptor subunits of GABA(A) was increased when schizophrenia was present. RELN mRNA was preferentially expressed in GABAergic interneurons of PFC, temporal cortex, hippocampus, and glutamatergic granule cells of cerebellum. A protein putatively functioning as an intracellular target for the signal-transduction cascade triggered by RELN protein released into the extracellular matrix is termed mouse disabled-1 (DAB1) and is expressed at comparable levels in the neuroplasm of the PFC and hippocampal pyramidal neurons, cerebellar Purkinje neurons of schizophrenia patients, and nonpsychiatric subjects; these three types of neurons do not express RELN protein. In the same samples of temporal cortex, we found a decrease in RELN protein of approximate to 50% but no changes in DAB1 protein expression. We also observed a large (up to 70%) decrease of GAD67 but only a small decrease of GAD65 protein content. These findings are interpreted within a neurodevelopmental/vulnerability "two-hit" model for the etiology of schizophrenia.