Arbabi Keon, Newton Dwight F, Oh Hyunjung, Davie Melanie C, Lewis David A, Wainberg Michael, Tripathy Shreejoy J, Sibille Etienne
The Krembil Centre for Neuroinformatics, Centre for Addiction & Mental Health, Toronto, ON, Canada.
Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
Mol Psychiatry. 2025 Mar;30(3):1057-1068. doi: 10.1038/s41380-024-02707-1. Epub 2024 Sep 5.
Psychiatric disorders such as major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are characterized by altered cognition and mood, brain functions that depend on information processing by cortical microcircuits. We hypothesized that psychiatric disorders would display cell type-specific transcriptional alterations in neuronal subpopulations that make up cortical microcircuits: excitatory pyramidal (PYR) neurons and vasoactive intestinal peptide- (VIP), somatostatin- (SST), and parvalbumin- (PVALB) expressing inhibitory interneurons. Using laser capture microdissection followed by RNA sequencing (LCM-seq), we performed cell type-specific molecular profiling of subgenual anterior cingulate cortex, a region implicated in mood and cognitive control. We sequenced libraries from 130 whole cells pooled per neuronal subtype (VIP, SST, PVALB, superficial and deep PYR) in 76 subjects from the University of Pittsburgh Brain Tissue Donation Program, evenly split between MDD, BD and SCZ subjects and healthy controls (totaling 380 bulk transcriptomes from ~50,000 neurons). We identified hundreds of differentially expressed (DE) genes and biological pathways across disorders and neuronal subtypes, with the vast majority in interneurons, particularly PVALB. While DE genes were unique to each cell type, there was a partial overlap across disorders for genes involved in the formation and maintenance of neuronal circuits. We observed coordinated alterations in biological pathways between select pairs of microcircuit cell types, also partially shared across disorders. Finally, DE genes coincided with known risk variants from psychiatric genome-wide association studies, suggesting cell type-specific convergence between genetic and transcriptomic risk for psychiatric disorders. Our study suggests transdiagnostic cortical microcircuit pathology in SCZ, BD, and MDD and sets the stage for larger-scale studies investigating how cell circuit-based changes contribute to shared psychiatric risk.
诸如重度抑郁症（MDD）、双相情感障碍（BD）和精神分裂症（SCZ）等精神疾病的特征是认知和情绪改变，而这些脑功能依赖于皮质微回路的信息处理。我们假设，精神疾病会在构成皮质微回路的神经元亚群中表现出细胞类型特异性的转录改变：兴奋性锥体（PYR）神经元以及表达血管活性肠肽（VIP）、生长抑素（SST）和小白蛋白（PVALB）的抑制性中间神经元。通过激光捕获显微切割术结合RNA测序（LCM-seq），我们对膝下前扣带回皮质进行了细胞类型特异性分子分析，该区域与情绪和认知控制有关。我们对来自匹兹堡大学脑组织捐赠项目的76名受试者中每个神经元亚型（VIP、SST、PVALB、浅层和深层PYR）汇集的130个全细胞文库进行了测序，这些受试者在MDD、BD和SCZ患者以及健康对照之间平均分配（总共来自约50,000个神经元的380个批量转录组）。我们在各种疾病和神经元亚型中鉴定出数百个差异表达（DE）基因和生物学途径，其中绝大多数存在于中间神经元中，尤其是PVALB。虽然DE基因在每种细胞类型中都是独特的，但参与神经元回路形成和维持的基因在不同疾病之间存在部分重叠。我们观察到选定的微回路细胞类型对之间生物学途径的协同改变，在不同疾病之间也有部分共享。最后，DE基因与精神疾病全基因组关联研究中的已知风险变异相吻合，表明精神疾病的遗传和转录组风险之间存在细胞类型特异性的趋同。我们的研究表明SCZ、BD和MDD中存在跨诊断的皮质微回路病理学，并为更大规模的研究奠定了基础，这些研究将探究基于细胞回路的变化如何导致共同的精神疾病风险。
