Role of GABA transporter 3 in GABAergic synaptic transmission at striatal output neurons

Striatal GABAergic signaling has been shown to be essential for basal ganglia output and proper motor performance. In the mouse neostriatum GABA transporter 1 (GAT‐1) was previously found to assist in the clearance of GABA from the extracellular space and influence both phasic and tonic GABAergic inhibition of medium‐sized striatal output neurons (SONs). It currently remains unknown whether GAT subtypes other than GAT‐1 participate in the modulation of GABAergic transmission in this brain structure. In this study, we aimed at assessing the role of GAT‐3 in the mouse neostriatum. To this end, we recorded GABAergic inhibitory postsynaptic currents (IPSCs) from SONs in brain slices at different developmental stages (postnatal days (P) 7‐9, 12‐14, and 28‐34) using the whole‐cell patch‐clamp technique. When applied under control conditions, SNAP‐5114 (40 μM), a specific GAT‐3 blocker, did not affect miniature or evoked IPSCs (m/eIPSCs) and produced no significant effect on tonic GABAA receptor‐mediated conductances in SONs. However, in the presence of NO‐711 (10 μM), a specific GAT‐1 blocker, SNAP‐5114 reduced mIPSC frequencies without affecting mIPSC amplitudes or kinetics. In addition, SNAP‐5114 reduced the mean amplitude of eIPSCs and increased the paired‐pulse ratio. These effects were entirely abolished by CGP55845 (1 μM), a specific GABAB receptor blocker, indicating that they were mediated by presynaptic GABAB receptors. Similar results were obtained from all age groups. We conclude that GAT‐3 is functionally expressed in the mouse neostriatum. Whereas an acute block of GAT‐3 under resting conditions is fully compensated for by GAT‐1, GAT‐3 might provide an additional uptake capacity when neuronal activity and GABA release are increased. Synapse 63:921–929, 2009. © 2009 Wiley‐Liss, Inc.