摘要

Obsessive compulsive disorder (OCD) is a severe illness that affects 2–3% of people worldwide. OCD neuroimaging studies have consistently shown abnormal activity in brain regions involved in decision-making (orbitofrontal cortex [OFC]) and action selection (striatum). However, little is known regarding molecular changes that may contribute to abnormal function.We therefore examined expression of synaptic genes in post-mortem human brain samples of these regions from eight pairs of unaffected comparison and OCD subjects. Total grey matter tissue samples were obtained from medial OFC (BA11), lateral OFC (BA47), head of caudate, and nucleus accumbens (NAc). Quantitative polymerase chain reaction (qPCR) was then performed on a panel of transcripts encoding proteins related to excitatory synaptic structure, excitatory synaptic receptors/transporters, and GABA synapses. Relative to unaffected comparison subjects, OCD subjects had significantly lower levels of several transcripts related to excitatory signaling in both cortical and striatal regions. However, a majority of transcripts encoding excitatory synaptic proteins were lower in OFC but not significantly different in striatum of OCD subjects. Composite transcript level measures supported these findings by revealing that reductions in transcripts encoding excitatory synaptic structure proteins and excitatory synaptic receptors/transporters occurred primarily in OFC of OCD subjects. In contrast, transcripts associated with inhibitory synaptic neurotransmission showed minor differences between groups. The observed lower levels of multiple glutamatergic transcripts across both medial and lateral OFC may suggest an upstream causal event. Together, these data provide the first evidence of molecular abnormalities in brain regions consistently implicated in OCD human imaging studies.

译文

强迫症（OCD）是一种严重的疾病，影响全世界2-3％的人。 OCD神经影像学研究一直显示参与决策（眶额皮质[OFC]）和动作选择（纹状体）的大脑区域的异常活动。然而，关于可能导致异常功能的分子变化知之甚少。因此，我们检查了来自8对未受影响的比较和OCD受试者的这些区域的死后人脑样品中突触基因的表达。总灰质组织样品获自内侧OFC（BA11），侧向OFC（BA47），尾状头和伏隔核（NAc）。然后对编码与兴奋性突触结构，兴奋性突触受体/转运蛋白和GABA突触相关的蛋白质的一组转录物进行定量聚合酶链反应（qPCR）。相对于未受影响的比较受试者，OCD受试者在皮质和纹状体区域中具有与兴奋性信号传导相关的几种转录物的水平显着较低。然而，编码兴奋性突触蛋白的大多数转录物在OFC中较低但在OCD受试者的纹状体中没有显着差异。复合转录物水平测量通过揭示编码兴奋性突触结构蛋白和兴奋性突触受体/转运蛋白的转录物的减少主要发生在OCD受试者的OFC中来支持这些发现。相反，与抑制性突触神经传递相关的转录物显示组间的微小差异。在内侧和外侧OFC中观察到的较低水平的多种谷氨酸能转录物可能提示上游因果事件。总之，这些数据提供了与OCD人类成像研究一致的大脑区域分子异常的第一个证据。