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The Gamma-aminobutyric acid type A receptor subunit delta (GABRD) is a structural component of specialized extrasynaptic GABA-A receptors, which function as ligand-gated chloride channels. These receptors mediate tonic inhibition, providing a continuous inhibitory tone that regulates the baseline excitability of neurons throughout the central nervous system. Expressed predominantly in the cerebellum, hippocampus, and thalamus, the delta subunit is a crucial determinant of the receptor’s high sensitivity to GABA and its characteristic low desensitization. GABRD is particularly sensitive to neurosteroids, making it a pivotal target for hormones and drugs that regulate mood, sleep, and stress responses. Pathogenic variants or altered expression of the GABRD gene are linked to several disorders, including idiopathic generalized epilepsy, neurodevelopmental conditions like autism, and postpartum depression. Therapeutically, the delta subunit is targeted by positive allosteric modulators such as ganaxolone and brexanolone to manage seizures and depressive symptoms. Additionally, recent research suggests that GABRD may play a role in non-neuronal processes, such as cell cycle regulation in breast and colon cancers.
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