Molecular mechanisms contributing to dendritic spine alterations in the prefrontal cortex of subjects with schizophrenia
Molecular mechanisms contributing to dendritic spine alterations in the prefrontal cortex of subjects with schizophrenia
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DOI：
10.1038/sj.mp.4001792
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发表时间：
2006-06-01
影响因子：
11
通讯作者：
Lewis, D. A.
中科院分区：
文献类型：
--
作者：
Hill, J. J.;Hashimoto, T.;Lewis, D. A.
尸检研究显示，精神分裂症患者的背外侧前额叶皮层（DLPFC）的树突棘密度降低。然而，可能导致这些改变的分子机制尚不清楚。最近对调节脊柱动力学的细胞内信号的研究已经确定了RhoGTdR家族的成员（例如，例如，在一个实施例中，Cdc42，Rac1，RhoA）作为脊柱结构的关键调节因子。此外，Duo和dreplant是分别对棘维持和棘形成至关重要的棘特异性蛋白。为了确定是否Cdc42，Rac1，RhoA，Duo或drexine的mRNA表达水平在精神分裂症中改变，组织切片含有DLPFC区9从15对匹配的精神分裂症受试者和对照组进行了原位杂交处理。这些mRNA的表达水平也与同一受试者的一个子集中的DLPFC棘密度相关。为了评估抗精神病药物对这些mRNA表达的潜在影响，在长期暴露于氟哌啶醇或奥氮平的猴中进行了类似的研究。与对照组相比，精神分裂症受试者的灰质中这些mRNA的表达均较低，尽管在多重比较校正后，只有Cdc42和Duo的减少仍显着。此外，棘密度与Duo（r = 0.73，P = 0.007）和Cdc42（r = 0.71，P = 0.009）mRNA的表达水平强相关。相反，Cdc42和Duo mRNA的表达水平在长期暴露于抗精神病药物的猴子中没有改变。总之，Cdc42和Duo mRNA的表达减少可能代表了导致精神分裂症患者DLPFC中树突棘密度降低的分子机制。
Postmortem studies have revealed reduced densities of dendritic spines in the dorsal lateral prefrontal cortex (DLPFC) of subjects with schizophrenia. However, the molecular mechanisms that might contribute to these alterations are unknown. Recent studies of the intracellular signals that regulate spine dynamics have identified members of the RhoGTPase family (e. g., Cdc42, Rac1, RhoA) as critical regulators of spine structure. In addition, Duo and drebrin are spine-specific proteins that are critical for spine maintenance and spine formation, respectively. In order to determine whether the mRNA expression levels of Cdc42, Rac1, RhoA, Duo or drebrin are altered in schizophrenia, tissue sections containing DLPFC area 9 from 15 matched pairs of subjects with schizophrenia and control subjects were processed for in situ hybridization. Expression levels of these mRNAs were also correlated with DLPFC spine density in a subset of the same subjects. In order to assess the potential influence of antipsychotic medications on the expression of these mRNAs, similar studies were conducted in monkeys chronically exposed to haloperidol or olanzapine. The expression of each of these mRNAs was lower in the gray matter of the subjects with schizophrenia compared to the control subjects, although only the reductions in Cdc42 and Duo remained significant after corrections for multiple comparisons. In addition, spine density was strongly correlated with the expression levels of both Duo (r = 0.73, P = 0.007) and Cdc42 (r = 0.71, P = 0.009) mRNAs. In contrast, the expression levels of Cdc42 and Duo mRNAs were not altered in monkeys chronically exposed to antipsychotic medications. In conclusion, reduced expression of Cdc42 and Duo mRNAs may represent molecular mechanisms that contribute to the decreased density of dendritic spines in the DLPFC of subjects with schizophrenia.