Single-cell dissection of schizophrenia reveals neurodevelopmental-synaptic axis and transcriptional resilience

Abstract

Schizophrenia is a devastating mental disorder with a high societal burden, complex pathophysiology, and diverse genetic and environmental risk factors. Its complexity, polygenicity, and small-effect-size and cell-type-specific contributors have hindered mechanistic elucidation and the search for new therapeutics. Here, we present the first single-cell dissection of schizophrenia, across 500,000+ cells from 48 postmortem human prefrontal cortex samples, including 24 schizophrenia cases and 24 controls. We annotate 20 cell types/states, providing a high-resolution atlas of schizophrenia-altered genes and pathways in each. We find neurons are the most affected cell type, with deep-layer cortico-cortical projection neurons and parvalbumin-expressing inhibitory neurons showing significant transcriptional changes converging on genetically-implicated regions. We discover a novel excitatory-neuron cell-state indicative of transcriptional resilience and enriched in schizophrenia subjects with less-perturbed transcriptional signatures. We identify key trans-acting factors as candidate drivers of observed transcriptional perturbations, including MEF2C, TCF4, SOX5, and SATB2, and map their binding patterns in postmortem human neurons. These factors regulate distinct gene sets underlying fetal neurodevelopment and adult synaptic function, bridging two leading models of schizophrenia pathogenesis. Our results provide the most detailed map to date for mechanistic understanding and therapeutic development in neuropsychiatric disorders.

Acetylated Chromatin Domains Link Chromosomal Organization to Cell- and Circuit-level Dysfunction in Schizophrenia and Bipolar Disorder

“…Such type of epigenetic pathology in developing PFC could extend beyond the level of histone acetylation, given that alterations in DNA cytosine methylation profiles in adult SCZ PFC frequently encompass regulatory sequences defined by dynamic methylation drifts during the transition from the pre-to the postnatal period 45 . Furthermore, the link between PFC glutamate neuron-specific CRD hyperacetylation in SCZ and BD as reported here broadly resonates with transcriptomics-focused studies reporting that in single nucleus-level expression profiling, glutamatergic neuron modules are up-regulated in the upper cortical layers of SCZ PFC 5,47 in addition to increased composite measures for glutamatergic transcripts in PFC of SCZ subjects 48 . Conversely, hypoacetylated CRDs were predominantly if not overwhelmingly composed of interneuron-and oligodendrocyte specific histone peaks with no enrichment for regulatory sequences conferring heritability risk.…”

Limited Association between Schizophrenia Genetic Risk Factors and Transcriptomic Features

“…In addition to transcriptomic features obtained from bulk-brain RNA-seq, cell type-specific DEGs were obtained from Ruzicka et al [ 14 ]. For a given cell type, we combined up- and downregulated genes to define DEGs, because there was a much smaller number of down- and upregulated genes identified by cell type-specific RNA-seq than were identified by bulk-brain RNA-seq.…”

Single-cell profiling of the human primary motor cortex in ALS and FTLD

“…To compare VENs and Betz cells at similar resolution, we used data from our recent single-cell profiling of the dorsolateral PFC 38 carried out in the context of schizophrenia, but focusing only on the subset of 24 pathologically normal individuals. Detailed clustering and annotation of 107,358 PFC excitatory neurons (Extended Data Fig.…”