Gamma-aminobutyric acid (GABA) is the neurotransmitter of the local inhibitory neurons that control neuronal excitability and network interactions in the cerebral cortex. Most of the cortical inhibitory effects of GABA are mediated by GABAA receptors. Cortical GABAergic mechanisms are important in epileptogenesis and provide a target of antiepileptic drug therapy. Over the past several years, there has been increasing understanding of the heterogeneous molecular structure, function, and modulation of the GABAA receptors and the functional consequences of mutations affecting specific receptor subunits linked with various epilepsy syndromes. This new information provides a further insight into the mechanisms of epileptogenesis and potential for development of subunit-selective antiepileptic drugs. The GABAA receptors are pentameric chloride (Cl−) channels formed by various combinations of different types of α (α1 to α6), β (β1 to β3), γ (γ1 to γ3), δ, e, π, θ, and ρ (ρ1 to ρ3) subunits1,2 (figure 1). The different subunit combinations result in a great functional heterogeneity of GABAA receptors.2,3 GABA binding triggers opening of an intrinsic Cl− channel, allowing the rapid flux of Cl−. Most neurons in the adult brain maintain a low intracellular Cl− concentration due to the activity of a K+/Cl− cotransporter, and therefore in most cases, GABAA receptor activation produces a net entry of Cl−. This elicits inhibitory postsynaptic potentials due to both the hyperpolarizing effect of Cl− influx and shunting of excitatory synaptic inputs, resulting in a decreased probability of generation of an action potential. The GABAA receptors have several modulatory allosteric binding sites for benzodiazepines, neurosteroids, barbiturates, and general anesthetics, and their function is also affected by phosphorylation and the presence of divalent ions, such as zinc. …