Unravelling GABA Dysfunction in Autism: Pathophysiological Insights and Emerging Treatments

Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition marked by deficits in social interaction, communication and repetitive behaviours. Emerging evidence implicates dysfunction in γ-aminobutyric acid (GABA) signalling, the brain's primary inhibitory neurotransmitter system, in the pathogenesis of ASD. GABAergic neurotransmission plays a pivotal role in neurodevelopment, particularly in balancing excitatory and inhibitory signalling, synaptic plasticity and neural circuit maturation. Dysregulation in GABA synthesis, receptor expression and transport has been observed in both clinical and preclinical models of ASD, leading to disrupted neuronal connectivity and atypical behavioural phenotypes. This review critically explores the alterations in GABAergic signalling in ASD, highlighting the role of various GABA receptor subtypes (GABA_AR, GABA_BR and GABA_CR) and associated transport and metabolic enzymes. The therapeutic implications of modulating GABAergic activity are also examined. Pharmacological agents, such as GABA receptor agonists, GABA reuptake inhibitors and GABA transaminase inhibitors, exhibit varied efficacy profiles. Among these, GABAB receptor agonists, including arbaclofen and baclofen, show the most promise in improving social behaviour and reducing core ASD symptoms. Conversely, some agents that elevate GABA levels, such as vigabatrin and valproic acid, may exacerbate ASD-like features under certain conditions. Collectively, the data suggest that targeted modulation of GABAergic pathways, particularly GABA_B receptor signalling, offers a viable avenue for therapeutic intervention in ASD. However, further mechanistic studies and well-designed clinical trials are required to elucidate the optimal strategies for harnessing GABA modulation in ASD management.