GABRB3 encodes the beta-3 subunit of GABA(A) receptors, heteropentameric ligand-gated chloride channels that mediate the inhibitory effects of gamma-aminobutyric acid (GABA), the brain's primary inhibitory neurotransmitter 12. The beta-3 subunit assembles with four other subunits around a central pore containing GABA binding sites at alpha-beta interfaces 34. Upon GABA activation, GABRB3-containing receptors permit selective chloride ion influx, hyperpolarizing the postsynaptic neuron and reducing action potential generation 25. GABRB3 mediates both synaptic and extrasynaptic GABAergic inhibition, with alpha-1/beta-3-containing receptors exhibiting synaptogenic activity 6. The subunit also participates in histamine regulation and somatosensory processing 73. Clinically, GABRB3 mutations cause severe epileptic encephalopathies, including infantile spasms, Lennox-Gastaut syndrome, and early developmental epileptic encephalopathy, with de novo mutations showing strong statistical association 8910. Notably, transmembrane domain variants associate with more severe phenotypes than N-terminal variants 9. GABRB3 dysfunction contributes to intellectual disability and autism spectrum disorder pathophysiology, partly through impaired somatosensory mechanotransduction during development 111213. GABRB3-knockout mice exhibit seizures and behavioral abnormalities resembling Angelman syndrome 14, providing direct evidence linking reduced GABA(A) receptor function to epileptogenesis.