NMDARs Drive the Expression of Neuropsychiatric Disorder Risk Genes Within GABAergic Interneuron Subtypes in the Juvenile Brain

Vivek Mahadevan; Apratim Mitra; Yajun Zhang; Xiaoqing Yuan; Areg Peltekian; Ramesh Chittajallu; Caroline Esnault; Dragan Maric; Christopher Rhodes; Kenneth A Pelkey; Ryan Dale; Timothy J Petros; Chris J McBain

doi:10.3389/fnmol.2021.712609

NMDARs Drive the Expression of Neuropsychiatric Disorder Risk Genes Within GABAergic Interneuron Subtypes in the Juvenile Brain

Front Mol Neurosci. 2021 Sep 14:14:712609. doi: 10.3389/fnmol.2021.712609. eCollection 2021.

Affiliations

¹ Section on Cellular and Synaptic Physiology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Bethesda, MD, United States.
² Bioinformatics and Scientific Programming Core, NICHD, Bethesda, MD, United States.
³ Unit on Cellular and Molecular Neurodevelopment, NICHD, Bethesda, MD, United States.
⁴ Flow and Imaging Cytometry Core Facility, National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, MD, United States.

Abstract

Medial ganglionic eminence (MGE)-derived parvalbumin (PV)+, somatostatin (SST)+and Neurogliaform (NGFC)-type cortical and hippocampal interneurons, have distinct molecular, anatomical, and physiological properties. However, the molecular mechanisms regulating their maturation remain poorly understood. Here, via single-cell transcriptomics, we show that the obligate NMDA-type glutamate receptor (NMDAR) subunit gene Grin1 mediates transcriptional regulation of gene expression in specific subtypes of MGE-derived interneurons, leading to altered subtype abundances. Notably, MGE-specific early developmental Grin1 loss results in a broad downregulation of diverse transcriptional, synaptogenic and membrane excitability regulatory programs in the juvenile brain. These widespread gene expression abnormalities mirror aberrations that are typically associated with neurodevelopmental disorders. Our study hence provides a road map for the systematic examination of NMDAR signaling in interneuron subtypes, revealing potential MGE-specific genetic targets that could instruct future therapies of psychiatric disorders.

Keywords: GABAergic interneurons; NMDAR-hypofunction; Ribotag-seq; medial ganglionic eminence; neurodevelopmental disorders; scRNAseq; schizophrenia; transcriptional regulation.