Hill J J, Hashimoto T, Lewis D A
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Mol Psychiatry. 2006 Jun;11(6):557-66. doi: 10.1038/sj.mp.4001792.
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.
尸检研究显示，精神分裂症患者背外侧前额叶皮质（DLPFC）中树突棘密度降低。然而，可能导致这些改变的分子机制尚不清楚。最近对调节棘突动力学的细胞内信号的研究已确定RhoGTPase家族成员（如Cdc42、Rac1、RhoA）是棘突结构的关键调节因子。此外，Duo和drebrin是分别对棘突维持和棘突形成至关重要的棘突特异性蛋白。为了确定精神分裂症患者中Cdc42、Rac1、RhoA、Duo或drebrin的mRNA表达水平是否发生改变，对15对匹配的精神分裂症患者和对照受试者的包含DLPFC 9区的组织切片进行原位杂交处理。在同一受试者的一个子集中，这些mRNA的表达水平也与DLPFC棘突密度相关。为了评估抗精神病药物对这些mRNA表达的潜在影响，对长期暴露于氟哌啶醇或奥氮平的猴子进行了类似研究。与对照受试者相比，精神分裂症患者灰质中这些mRNA的表达均较低，尽管在进行多重比较校正后，只有Cdc42和Duo的降低仍具有统计学意义。此外，棘突密度与Duo（r=0.73，P=0.007）和Cdc42（r=0.71，P=0.009）mRNA的表达水平均密切相关。相比之下，长期暴露于抗精神病药物的猴子中Cdc42和Duo mRNA的表达水平未发生改变。总之，Cdc42和Duo mRNA表达降低可能是导致精神分裂症患者DLPFC中树突棘密度降低的分子机制。
