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.

重度抑郁症 (MDD)、双相情感障碍 (BD) 和精神分裂症 (SCZ) 等精神疾病的特点是认知和情绪改变，以及依赖于皮质微电路信息处理的大脑功能。我们假设精神疾病会在构成皮质微电路的神经元亚群中表现出细胞类型特异性转录改变：兴奋性锥体（PYR）神经元和血管活性肠肽（VIP）、生长抑素（SST）和小白蛋白（PVALB）表达抑制性中间神经元。使用激光捕获显微切割和 RNA 测序 (LCM-seq)，我们对膝下前扣带皮层（与情绪和认知控制有关的区域）进行了细胞类型特异性分子分析。我们对来自匹兹堡大学脑组织捐赠计划的 76 名受试者的每个神经元亚型（VIP、SST、PVALB、浅表和深部 PYR）的 130 个全细胞库进行了测序，这些受试者平均分为 MDD、BD 和 SCZ 受试者以及健康对照（总计来自约 50,000 个神经元的 380 个批量转录组）。我们鉴定了数百个跨疾病和神经元亚型的差异表达 (DE) 基因和生物通路，其中绝大多数位于中间神经元，特别是 PVALB。虽然 DE 基因对于每种细胞类型都是独特的，但参与神经元回路形成和维持的基因在疾病之间存在部分重叠。我们观察到选定的微电路细胞类型对之间生物途径的协调变化，这些变化在各种疾病中也有部分共享。 最后，DE 基因与精神科全基因组关联研究中已知的风险变异一致，表明精神疾病的遗传风险和转录风险之间存在细胞类型特异性趋同。我们的研究提出了 SCZ、BD 和 MDD 的跨诊断皮质微电路病理学，并为更大规模的研究奠定了基础，调查基于细胞电路的变化如何导致共同的精神风险。