Single-nuclei transcriptomics of schizophrenia prefrontal cortex primarily implicates neuronal subtypes

Transcriptomic studies of bulk neural tissue homogenates from persons with schizophrenia and controls have identified differential expressed genes in multiple brain regions. However, the heterogeneous nature prevents identification of relevant cell types. This study utilized single-nuclei transcriptomics of ∼311,000 nuclei from frozen human postmortem dorsolateral prefrontal cortex samples from individuals with schizophrenia (n = 14) and controls (n = 16). 2,846 differential expression events were identified in 2,195 unique genes in 19 of 24 transcriptomically-distinct cell populations. ∼97% of differential expressed genes occurred in five neuronal cell types, with ∼63% occurring in a subtype of PVALB+ inhibitory neurons and HTR2C+ layer V excitatory neurons. Differential expressed genes were enriched for genes associated with schizophrenia GWAS loci and cluster-specific changes in canonical pathways, upstream regulators and causal networks were identified. These results demonstrate cell type specific changes in the context of schizophrenia.