Altered expression of CDC42 signaling pathway components in cortical layer 3 pyramidal cells in schizophrenia.
Altered expression of CDC42 signaling pathway components in cortical layer 3 pyramidal cells in schizophrenia.
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DOI：
10.1016/j.biopsych.2015.03.030
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发表时间：
2015-12-01
影响因子：
10.6
通讯作者：
Lewis DA
中科院分区：
文献类型：
--
作者：
Datta D;Arion D;Corradi JP;Lewis DA
精神分裂症患者认知功能障碍与背外侧前额叶皮层（DLPFC）深层3锥体细胞树突棘密度降低有关。这些变化似乎反映了脊柱形成和维持所需的肌动蛋白细胞骨架的失调。与这一想法一致，先前在精神分裂症受试者的DLPFC灰质中报道了CDC 42（细胞分裂周期42）-CDC 42效应蛋白信号通路（肌动蛋白细胞骨架的关键组织者）中基因表达的改变。在这里，我们研究了精神分裂症的CDC 42-PAK-LIMK信号通路的完整性，在DLPFC深层3的层和细胞类型特异性的方式。使用激光显微切割，我们收集了来自56对配对的精神分裂症和对照受试者的DLPFC深层3的样本，并通过qPCR测量了CDC 42-PAK-LIMK通路mRNA的水平。这些相同的成绩单也定量微阵列样品中的单独显微解剖的深层3锥体细胞从一个子集的相同的主题和抗精神病药物暴露的猴子。相对于对照受试者，CDC 42 EP 4，LIMK 1，LIMK 2，ARHGDIA和PAK 3 mRNA水平在精神分裂症受试者的层流和细胞样本中显著上调。与此相反，CDC 42和PAK 1 mRNA水平显着下调，特别是在深层3锥体细胞。这些差异不归因于精神药物或其他共病因素。本研究和先前研究的结果集中在CDC 42信号通路的协同改变上，这种改变可能使肌动蛋白动力学不稳定，并优先在精神分裂症的深层3锥体细胞中产生棘缺陷。
Cognitive dysfunction in schizophrenia is associated with a lower density of dendritic spines on deep layer 3 pyramidal cells in the dorsolateral prefrontal cortex (DLPFC). These alterations appear to reflect dysregulation of the actin cytoskeleton required for spine formation and maintenance. Consistent with this idea, altered expression of genes in the CDC42 (cell division cycle 42)-CDC42 effector protein signaling pathway, a key organizer of the actin cytoskeleton, was previously reported in DLPFC gray matter from subjects with schizophrenia. Here, we examined the integrity in schizophrenia of the CDC42-PAK-LIMK signaling pathway in a layer- and cell type-specific fashion in DLPFC deep layer 3. Using laser microdissection, we collected samples of DLPFC deep layer 3 from 56 matched pairs of schizophrenia and comparison subjects and measured levels of CDC42-PAK-LIMK pathway mRNAs by qPCR. These same transcripts were also quantified by microarray in samples of individually microdissected deep layer 3 pyramidal cells from a subset of the same subjects and from antipsychotic-exposed monkeys. Relative to comparison subjects, CDC42EP4, LIMK1, LIMK2, ARHGDIA and PAK3 mRNA levels were significantly up-regulated in schizophrenia subjects in both laminar and cellular samples. In contrast, CDC42 and PAK1 mRNA levels were significantly down-regulated specifically in deep layer 3 pyramidal cells. These differences were not attributable to psychotropic medications or other co-morbid factors. Findings from the present and prior studies converge on synergistic alterations in CDC42 signaling pathway that could destabilize actin dynamics and produce spine deficits preferentially in deep layer 3 pyramidal cells in schizophrenia.