Neurogenomics Division, Translational Genomics Research Institute (TGen), Phoenix, Arizona, USA.
Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, Utah, USA.
CNS Neurosci Ther. 2023 Nov;29(11):3173-3182. doi: 10.1111/cns.14283. Epub 2023 Jun 2.
Antisocial personality disorder (ASPD) and conduct disorder (CD) are characterized by a persistent pattern of violations of societal norms and others' rights. Ample evidence shows that the pathophysiology of these disorders is contributed by orbitofrontal cortex (OFC) alterations, yet the underlying molecular mechanisms remain elusive. To address this knowledge gap, we performed the first-ever RNA sequencing study of postmortem OFC samples from subjects with a lifetime diagnosis of ASPD and/or CD.
The transcriptomic profiles of OFC samples from subjects with ASPD and/or CD were compared to those of unaffected age-matched controls (n = 9/group).
The OFC of ASPD/CD-affected subjects displayed significant differences in the expression of 328 genes. Further gene-ontology analyses revealed an extensive downregulation of excitatory neuron transcripts and upregulation of astrocyte transcripts. These alterations were paralleled by significant modifications in synaptic regulation and glutamatergic neurotransmission pathways.
These preliminary findings suggest that ASPD and CD feature a complex array of functional deficits in the pyramidal neurons and astrocytes of the OFC. In turn, these aberrances may contribute to the reduced OFC connectivity observed in antisocial subjects. Future analyses on larger cohorts are needed to validate these results.
反社会型人格障碍 (ASPD) 和品行障碍 (CD) 的特征是持续违反社会规范和他人权利的模式。大量证据表明，这些障碍的病理生理学是由眶额叶皮层 (OFC) 改变引起的，但潜在的分子机制仍不清楚。为了解决这一知识空白，我们对有终生 ASPD 和/或 CD 诊断的受试者的死后 OFC 样本进行了首次 RNA 测序研究。
将 ASPD 和/或 CD 受试者的 OFC 样本的转录组谱与未受影响的年龄匹配对照者（每组 n = 9）进行比较。
ASPD/CD 受影响受试者的 OFC 显示出 328 个基因表达的显著差异。进一步的基因本体分析显示兴奋性神经元转录物的广泛下调和星形胶质细胞转录物的上调。这些改变与突触调节和谷氨酸能神经递质传递途径的显著改变平行。
这些初步发现表明，ASPD 和 CD 特征是 OFC 中的锥体神经元和星形胶质细胞出现一系列复杂的功能缺陷。反过来，这些异常可能导致反社会受试者中观察到的 OFC 连接减少。需要对更大的队列进行进一步的分析来验证这些结果。
