What Is the Role of GABA Transporters in Seizures?

The brain utilizes γ‐aminobutyric acid (GABA) as its primary inhibitory neurotransmitter to control neuronal excitability and modulate the ongoing activity of neuronal ensembles. GABA controls the generation of membrane potential oscillations, which provide the time window for integration of synaptic inputs and generation of activity patterns in neuronal networks. These effects require a fine control of GABAA and GABAB receptor activation, which, in turn, depends on both the precise timing of GABA release from presynaptic terminals and GABA clearance from the extracellular space. GABA is synthesized in presynaptic terminals from glutamate via the glutamic acid decarboxylases 65 and 67 and is incorporated in synaptic vesicles via the vesicular GABA transporter, referred to as vesicular inhibitory amino-acid transporter (VIAAT) as it also mediates vesicular uptake of glycine1 (Figure). The clearance of GABA after release depends on its uptake by specific GABA transporters (GATs), including GAT-1, expressed predominantly in axons and presynaptic terminals, and GAT-3, expressed primarily in astrocytes.2,3 By controlling extracellular GABA levels, GATs have a major role in regulating tonic and phasic inhibition in the cerebral cortex, hippocampus, thalamus, and other areas.2,3 Experimental studies in mouse models indicate a major role of GATs in regulating cortical excitability and predisposition to seizures. Mutations affecting the GABA transporters have been linked to different seizure phenotypes. For example, loss of function mutations of the SLC6A1 gene encoding GAT-1 have been associated with epilepsy with myoclonic-atonic seizures and with absence seizures.4,5