GABRA4 encodes the alpha-4 subunit of GABA_A receptors, heteropentameric ligand-gated chloride channels that mediate inhibitory neurotransmission in the brain 1. When activated by GABA, these receptors selectively permit chloride anion influx across the cell membrane, reducing neuronal excitability 1. Alpha-4-containing GABA_A receptors are predominantly extrasynaptic and contribute to tonic inhibition in dentate granule cells and thalamic neurons, regulating network excitability 1. Notably, GABA_A receptors containing alpha-4, beta-3, and delta subunits can simultaneously bind GABA and histamine, potentially regulating sleep-wake cycles 1. Clinically, GABRA4 dysfunction associates with multiple neurological conditions. De novo missense variants in GABRA4 cause early-onset drug-resistant epilepsy with neurodevelopmental abnormalities, exhibiting accelerated receptor desensitization and loss of neurosteroid-mediated seizure protection 2. Gabra4 knockout mice display autistic-like behaviors alongside enhanced spatial memory and reduced seizure susceptibility, with dysregulation of NMDAR pathways potentially underlying these phenotypes 3. Additionally, GABRA4 expression is upregulated following status epilepticus through Egr3-mediated transcriptional regulation, suggesting a critical role in seizure-induced neuroadaptation 4. Genetic variation in GABRA4 may also influence migraine susceptibility and responsiveness to ethanol-induced migraine triggers 5, while miR-33-mediated suppression of GABRA4 enhances sympathetic nervous system activity and adaptive thermogenesis 6.