GABA_A receptor dysfunction in autism spectrum disorder: molecular mechanisms and therapeutic opportunities

Autism spectrum disorder (ASD) comprises diverse neurodevelopmental trajectories in which altered circuit dynamics converge on a disturbance of excitation-inhibition balance. Genetic, postmortem, neuroimaging, and model-system evidence implicates γ-aminobutyric acid type A (GABA_A) receptors as a major molecular node within this imbalance. ASD has been associated with changes in GABA_A receptor subunit expression and assembly, notably within 15q11-q13 clusters, impaired receptor trafficking and synaptic anchoring, and a shift in the relative contribution of phasic (synaptic, containing the γ2 subunit) versus tonic (extra-synaptic with δ or ρ) inhibition. Postmortem studies reported reduced expression of GABA_A subunits, which correlates with decreased expression of glutamic acid decarboxylase 65/67, interneuron loss, particularly in parvalbumin networks that support gamma oscillations, and disrupted chloride homeostasis, which can delay the developmental "GABA switch" from depolarizing to hyperpolarizing signalling. Here, we review mechanistic advances across environmental and monogenic ASD models [e.g., prenatal valproate exposure, maternal immune activation, shank3 (SH3 and multiple ankyrin repeat domains 3), fmr1 (fragile X messenger ribonucleoprotein 1), and mecp2 (methyl-CpG binding protein 2) alongside human biomarker studies using proton magnetic resonance spectroscopy and positron emission tomography, highlighting how GABA receptor subtype- and circuit-specific inhibitory deficits map onto sensory, social, cognitive, and comorbid seizure phenotypes. We evaluate emerging therapeutic strategies that move beyond nonselective sedation, including α2/α3-and α5-preferring positive allosteric modulators, neurosteroid-based enhancers of tonic inhibition, and interventions targeting sodium-potassium chloride cotransporter 1/potassium chloride cotransporter 2-regulated chloride gradients, as well as activity-dependent approaches such as environmental enrichment. Finally, we outline priorities for precision translation: multimodal biomarker-guided stratification, developmentally timed intervention windows, and trials aligned to receptor subtype pharmacology and circuit endpoints. This review integrates molecular and translational research on GABA_A receptor dysfunction in ASD, emphasizing key mechanistic insights and potential therapeutic approaches. To develop precise GABAergic treatments, a comprehensive strategy that includes molecular profiling, biomarker-guided clinical trials, and insights from developmental neuroscience is necessary.