The Role of GABA Pathway Components in Pathogenesis of Neurodevelopmental Disorders.

γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system (CNS), regulates neuronal excitability, synaptic plasticity, and oscillatory activity essential for cognition, emotion, and behavior. Disruptions in GABAergic signaling are increasingly recognized as key contributors to a range of neurodevelopmental disorders (NDDs), including schizophrenia (SZ), autism spectrum disorder (ASD), major depressive disorder (MDD), bipolar disorder (BD), and intellectual disability (ID). In this review, we analyze the data available from the literature concerning the components of the GABA pathway. We describe the main steps of GABA metabolism, including GABA synthesis and release, GABA receptors neurotransmission, GABA reuptake and catabolism, and evaluate their involvement in the pathogenesis of neurodevelopmental disorders. We suggest the possibility of existence of so far undescribed mechanisms which maintain the concentrations of GABA at a relatively physiological level when the function of glutamic acid decarboxylases is compromised by mutations. Searching for these mechanisms could be important for better understanding neurodevelopment and could give a clue for future searches for new therapeutic approaches for treating or alleviating the symptoms of BD and SZ. We also argue that the metabolic stage of the GABA pathway has only a minor direct effect on GABA signaling and rather causes clinical effects due to accumulation of neurotoxic byproducts.