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GAT-3 Transporters Regulate Inhibition in the Neocortex

Department of Rehabilitation Medicine, University of Washington School of Medicine, Seattle, Washington

Submitted 24 April 2005; accepted in final form 24 August 2005

The role of GAT-3 transporters in regulating GABA_A receptor-mediated inhibition was examined in the rat neocortex using an in vitro slice preparation. Pharmacologically isolated GABA_A receptor-mediated responses were recorded from layer V neocortical pyramidal cells, and the effects of SNAP-5114, a GAT-3 GABA transporter-selective antagonist, were evaluated. Application of SNAP-5114 resulted in a reversible increase in the amplitude of an evoked GABA_A response in most cells examined, although no effect on the decay time was observed. Examination of the spontaneous output of inhibitory interneurons revealed a reversible increase in the frequency and amplitude of spontaneous inhibitory synaptic currents as a consequence of GAT-3 inhibition. This effect of GAT-3 inhibition on spontaneous inhibitory events was action potential-dependent because no such increases were observed when SNAP-5114 was applied in the presence of TTX. These results demonstrate that GAT-3 transporters regulate inhibitory interneuron output in the neocortex. The increase in inhibitory interneuron excitability resulting from application of SNAP-5114 suggests that inhibition of GAT-3 transporter function results in a reduction in ambient GABA levels, possibly by a reduction in carrier-mediated GABA release via the GAT-3 transporter.

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