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J Neurophysiol (June 29, 2005). doi:10.1152/jn.00520.2005
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00520.2005v1
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Submitted on May 19, 2005
Accepted on June 15, 2005

Subtype-specific GABA Transporter Antagonists Synergistically Modulate Phasic and Tonic GABAA Conductances in Rat Neocortex

Sotirios Keros and John J. Hablitz*

* To whom correspondence should be addressed. E-mail: jhablitz{at}uab.edu.

GABAergic inhibition in the brain can be classified as either phasic or tonic. GABA uptake via GABA transporters (GATs) can limit the time course of phasic currents arising from endogenous and exogenous GABA, as well as decrease a tonically active GABA current. GABA transporter subtypes 1 and 3 (GAT-1 and GAT-3) are the most heavily expressed of the 4 known GAT subtypes. The role of GATs in shaping GABA currents in the neocortex has not been explored. We obtained patch-clamp recordings from layer II/III pyramidal cells and layer I interneurons in rat sensorimotor cortex. We found that selective GAT-1 inhibition with NO711 decreased the amplitude and increased the decay time of evoked inhibitory postsynaptic currents (IPSCs) but had no effect on the tonic current or spontaneous IPSCs. GAT-2/3 inhibition with SNAP-5114 had no effect on IPSCs or the tonic current. Coapplication of NO711 and SNAP-5114 markedly increased tonic currents and synergistically decreased IPSC amplitudes and increased IPSC decay times. Spontaneous IPSCs were not resolvable with co-application of NO711 and SNAP-5114. The effects of the non-selective GAT antagonist nipecotic acid were similar to those of NO711 and SNAP-5114 together. We conclude that synaptic GABA levels in neocortical neurons are controlled primarily by GAT-1, but that GAT-1 and GAT-2/3 work together extrasynaptically to limit tonic currents. Inhibition of any one GAT subtype does not increase the tonic current, presumably as a result of increased activity of the remaining transporters. Thus, neocortical GAT-1 and GAT-2/3 have distinct but overlapping roles in modulating GABA conductances.




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