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Adv Pharmacol. 2010;58:175-204. doi: 10.1016/S1054-3589(10)58008-6.

GABA transporter GAT1: a crucial determinant of GABAB receptor activation in cortical circuits?

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Department of Psychiatry, Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.


The GABA transporter 1 (GAT1), the main plasma membrane GABA transporter in brain tissue, mediates translocation of GABA from the extracellular to the intracellular space. Whereas GAT1-mediated uptake could generally terminate the synaptic effects of GABA, recent studies suggest a more complex physiological role. This chapter reviews evidence suggesting that in hippocampal and neocortical circuits, GAT1-mediated GABA transport regulates the electrophysiological effects of GABA(B) receptor (GABA(B)R) activation by synaptically-released GABA. Contrasting with synaptic GABA(A) receptors, GABA(B)Rs display high GABA binding affinity, slow G protein-coupled mediated signaling, and a predominantly extrasynaptic localization. Such GABA(B)R properties determine production of slow inhibitory postsynaptic potentials (IPSPs) and slow presynaptic effects. Such effects possibly require diffusion of GABA far away from the release sites, and consequently both GABA(B)R-mediated IPSPs and presynaptic effects are strongly enhanced when GAT1-mediated uptake is blocked. Studies are reviewed here which indicate that GABA(B)R-mediated IPSPs seem to be produced by dendrite-targeting GABA neurons including specifically, although perhaps not exclusively, the neurogliaform cell class. In contrast, the GABA interneuron subtypes that synapse onto the perisomatic membrane of pyramidal cells mostly signal via synaptic GABA(A)Rs. This chapter reviews data suggesting that neurogliaform cells produce electrophysiological effects onto other neurons in the cortical cell network via GABA(B)R-mediated volume transmission that is highly regulated by GAT1 activity. Therefore, the role of GAT1 in controlling GABA(B)R-mediated signaling is markedly different from its regulation of GABA(A)R-mediated fast synaptic transmission.

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