Transcriptomic pathology of neocortical microcircuit cell types across psychiatric disorders

Abstract Background Psychiatric disorders like 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. Methods We performed cell type-specific molecular profiling of subgenual anterior cingulate cortex, a region implicated in mood and cognitive control, using laser capture microdissection followed by RNA sequencing (LCM-seq). 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. Results We identified hundreds of differentially expressed (DE) genes and biological pathways across disorders and neuronal subtypes, with the vast majority in inhibitory neuron types, primarily PVALB. DE genes were distinct across cell types, but partially shared across disorders, with nearly all shared genes involved in the formation and maintenance of neuronal circuits. Coordinated alterations in biological pathways were observed between select pairs of microcircuit cell types and partially shared across disorders. Finally, DE genes coincided with known risk variants from psychiatric genome-wide association studies, indicating cell type-specific convergence between genetic and transcriptomic risk for psychiatric disorders. Conclusions We present the first cell type-specific dataset of cortical microcircuit gene expression across multiple psychiatric disorders. Each neuronal subtype displayed unique dysregulation signatures, some shared across cell types and disorders. Inhibitory interneurons showed more dysregulation than excitatory pyramidal neurons. 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.