Cell Type-Specific Gene Expression of Alpha 5 Subunit-Containing Gamma-Aminobutyric Acid Subtype A Receptors in Human and Mouse Frontal Cortex

Xiyue Hu; Brad R Rocco; Corey Fee; Etienne Sibille

doi:10.1159/000495840

Cell Type-Specific Gene Expression of Alpha 5 Subunit-Containing Gamma-Aminobutyric Acid Subtype A Receptors in Human and Mouse Frontal Cortex

Mol Neuropsychiatry. 2019 Feb;4(4):204-215. doi: 10.1159/000495840. Epub 2019 Jan 23.

Authors

Xiyue Hu^{1

2}, Brad R Rocco¹, Corey Fee^{1

2}, Etienne Sibille^{1

2

3}

Affiliations

¹ Campbell Family Mental Health Research Institute of CAMH, Toronto, Ontario, Canada.
² Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
³ Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.

Abstract

Converging evidence suggests that deficits in somatostatin (SST)-expressing neuron signaling contributes to major depressive disorder. Preclinical studies show that enhancing this signaling, specifically at α5 subunit-containing γ-ami-nobutyric acid subtype A receptors (α5-GABA^ARs), provides a potential means to overcome low SST neuron function. The cortical microcircuit comprises multiple subtypes of inhibitory γ-aminobutyric acid (GABA) neurons and excitatory pyramidal cells (PYCs). In this study, multilabel fluorescence in situ hybridization was used to characterize α5-GABA^AR gene expression in PYCs and three GABAergic neuron subgroups - vasoactive intestinal peptide (VIP)-, SST-, and parvalbumin (PV)-expressing cells - in the human and mouse frontal cortex. Across species, we found the majority of gene expression in PYCs (human: 39.7%; mouse: 54.14%), less abundant expression in PV neurons (human: 20%; mouse: 16.33%), and no expression in VIP neurons (0%). Only human SST cells expressed GABRA5, albeit at low levels (human: 8.3%; mouse: 0%). Together, this localization suggests potential roles for α5-GABA^ARs within the cortical microcircuit: (1) regulators of PYCs, (2) regulators of PV cell activity across species, and (3) sparse regulators of SST cell inhibition in humans. These results will advance our ability to predict the effects of pharmacological agents targeting α5-GABA^ARs, which have shown therapeutic potential in preclinical animal models.

Keywords: Cortical microcircuitry; Fluorescence in situ hybridization; GABRA5; Gamma-aminobutyric acid; Somatostatin.