Transcriptomic pathology of neocortical microcircuit cell types across psychiatric disorders.

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.