Abstract
The long-lasting actions of the inhibitory neurotransmitter GABA result from the activation of metabotropic GABA(B) receptors. Enhanced GABA(B)-mediated IPSCs are critical for the generation of generalized thalamocortical seizures. Here, we demonstrate that GABA(B)-mediated IPSCs recorded in the thalamus are primarily defined by GABA diffusion and activation of distal extrasynaptic receptors potentially up to tens of micrometers from synapses. We also show that this diffusion is differentially regulated by two astrocytic GABA transporters, GAT1 and GAT3, which are localized near and far from synapses, respectively. A biologically constrained model of GABA diffusion and uptake shows how the two GATs differentially modulate amplitude and duration of GABA(B) IPSCs. Specifically, the perisynaptic expression of GAT1 enables it to regulate GABA levels near synapses and selectively modulate peak IPSC amplitude, which is primarily dependent on perisynaptic receptor occupancy. GAT3 expression, however, is broader and includes distal extrasynaptic regions. As such, GAT3 acts as a gatekeeper to prevent diffusion of GABA away from synapses toward extrasynaptic regions that contain a potentially enormous pool of GABA(B) receptors. Targeting this gatekeeper function may provide new pharmacotherapeutic opportunities to prevent the excessive GABA(B) receptor activation that appears necessary for thalamic seizure generation.