Distinctive transcriptome alterations of prefrontal pyramidal neurons in schizophrenia and schizoaffective disorder.
Distinctive transcriptome alterations of prefrontal pyramidal neurons in schizophrenia and schizoaffective disorder.
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DOI：
10.1038/mp.2014.171
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发表时间：
2015-11
影响因子：
11
通讯作者：
Lewis, D. A.
中科院分区：
文献类型：
--
作者：
Arion, D.;Corradi, J. P.;Tang, S.;Datta, D.;Boothe, F.;He, A.;Cacace, A. M.;Zaczek, R.;Albright, C. F.;Tseng, G.;Lewis, D. A.
精神分裂症与反映背外侧前额叶皮层（DLPFC）回路功能障碍的工作记忆改变有关。工作记忆依赖于DLPFC第3层兴奋性锥体细胞的活动，在较小程度上依赖于第5层。虽然许多研究已经分析了精神分裂症患者DLPFC灰质中的基因表达，但对这两个锥体细胞群体中细胞类型特异性转录本的表达知之甚少。我们假设，特别是在DLPFC层3或5锥体细胞中询问基因表达将揭示新的和/或更强大的精神分裂症相关的差异，这将为疾病中锥体细胞功能障碍的性质提供新的见解。我们还试图确定其他变量的影响，如情感障碍的诊断或死亡时的药物使用，对锥体神经元基因表达模式的影响。采用激光显微切割技术，对36例精神分裂症或情感性精神障碍患者和36例正常对照者的DLPFC第3层或第5层锥体细胞进行了分离。通过微阵列对来自细胞集合的mRNA进行转录组谱分析，然后进行qPCR验证。参与线粒体（MT）或泛素-蛋白酶体系统（UPS）功能的基因表达在患者组中显著下调（MT相关和UPS相关途径的p值分别为<10−7和<10−5）。MT相关的基因改变在第3层锥体细胞中更为突出，而UPS相关的基因改变在第5层锥体细胞中更为突出。这些改变中的许多在来自相同受试者的DLPFC灰质样品中不存在，或发现程度较低，表明它们是锥体细胞特异性的。此外，这些发现主要反映了精神分裂症受试者的改变，在情感性精神障碍受试者中不存在或存在程度较低（情感性精神障碍的诊断是最显著的协变量，p<10−6），并且不能归因于经常与精神分裂症共病的因素。总之，我们的研究结果揭示了MT和UPS相关基因的表达缺陷，具体到第3层和/或第5层锥体细胞在精神分裂症患者的DLPFC。这些细胞类型特异性转录组特征不是情感障碍的特征，为临床表型差异提供了潜在的分子细胞基础。
Schizophrenia is associated with alterations in working memory that reflect dysfunction of dorsolateral prefrontal cortex (DLPFC) circuitry. Working memory depends on the activity of excitatory pyramidal cells in DLPFC layer 3, and to a lesser extent in layer 5. Although many studies have profiled gene expression in DLPFC gray matter in schizophrenia, little is known about cell type-specific transcript expression in these two populations of pyramidal cells. We hypothesized that interrogating gene expression specifically in DLPFC layer 3 or 5 pyramidal cells would reveal new and/or more robust schizophrenia-associated differences that would provide new insights into the nature of pyramidal cell dysfunction in the illness. We also sought to determine the impact of other variables, such as a diagnosis of schizoaffective disorder or medication use at time of death, on the patterns of gene expression in pyramidal neurons. Individual pyramidal cells in DLPFC layers 3 or 5 were captured by laser microdissection from 36 subjects with schizophrenia or schizoaffective disorder and matched normal comparison subjects. The mRNA from cell collections was subjected to transcriptome profiling by microarray followed by qPCR validation. Expression of genes involved in mitochondrial (MT) or ubiquitin-proteasome system (UPS) functions were markedly down-regulated in the patient group (p values for MT-related and UPS-related pathways were <10−7 and <10−5 respectively). MT-related gene alterations were more prominent in layer 3 pyramidal cells, whereas UPS-related gene alterations were more prominent in layer 5 pyramidal cells. Many of these alterations were not present, or found to a lesser degree, in samples of DLPFC gray matter from the same subjects, suggesting that they are pyramidal cell-specific. Furthermore, these findings principally reflected alterations in the schizophrenia subjects, were not present or present to a lesser degree in the schizoaffective disorder subjects (diagnosis of schizoaffective disorder was the most significant covariate, p<10−6), and were not attributable to factors frequently comorbid with schizophrenia. In summary, our findings reveal expression deficits in MT- and UPS-related genes specific to layer 3 and/or layer 5 pyramidal cells in the DLPFC of schizophrenia subjects. These cell type-specific transcriptome signatures are not characteristic of schizoaffective disorder, providing a potential molecular-cellular basis of differences in clinical phenotypes.
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影响因子：
3.3
作者：
Glausier, J. R.;Lewis, D. A.
通讯作者：
Lewis, D. A.
影响因子：
3.7
作者：
Baxter, Kristin Kathleen;Uittenbogaard, Martine;Chiaramello, Anne
通讯作者：
Chiaramello, Anne
影响因子：
2.5
作者：
Gruber, Oliver;Gruber, Eva;Falkai, Peter
通讯作者：
Falkai, Peter
影响因子：
11
作者：
Hill, J. J.;Hashimoto, T.;Lewis, D. A.
通讯作者：
Lewis, D. A.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y