Transcriptional Profiles of Somatostatin and Parvalbumin Interneuron Subtypes in the Human Dorsolateral Prefrontal Cortex: Implications for Schizophrenia.

Abstract

Alterations in the somatostatin (<i>SST</i>) and parvalbumin (<i>PVALB</i>) classes of inhibitory GABAergic interneurons in the dorsolateral prefrontal cortex (DLPFC) are thought to contribute to the core cognitive impairments of schizophrenia. Both classes of interneurons are composed of multiple subtypes, but the distinguishing features and relative proportions of these subtypes have not been determined in the DLPFC. The aim of this study is to provide a comprehensive analysis of these subtypes from young and middle-age adults with no known psychiatric disorders. The authors used single-nucleus RNA sequencing to determine the transcriptional profiles of interneuron subtypes in DLPFC tissue samples from discovery and validation cohorts; fluorescent in situ hybridization to validate selected findings; and comparisons of transcriptome and electrophysiology data from the Allen Brain Atlas to infer functional properties of selected subtypes. The relative proportions of five major interneuron classes and of 37 interneuron subtypes were highly consistent across 19 individuals. Eleven <i>SST</i> subtypes were identified, including two rare subtypes that likely produce dopamine or regulate blood flow, and a subtype derived from the caudal ganglionic eminence. Among the nine <i>PVALB</i> subtypes identified, chandelier cells were transcriptionally distinct from <i>PVALB</i> basket cells (PVBCs) and PVBC subtypes. Moreover, subsets of PVBCs were distinguished by high versus low <i>PVALB</i> expression and had distinctive molecular features consistent with differences in anatomical (i.e., perineuronal nets) and electrophysiological (i.e., firing properties) characteristics. The robust identification of discrete subtypes of <i>SST</i> and <i>PVALB</i> interneurons in the DLPFC from young and middle-age adults with no known psychiatric disorders provides the means to determine which specific subtypes could be altered in proportional representation and/or gene expression in schizophrenia.