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The Journal of Neuroscience, April 15, 2001, 21(8):2630-2639

GABA Transaminase Inhibition Induces Spontaneous and Enhances Depolarization-Evoked GABA Efflux via Reversal of the GABA Transporter

Yuanming Wu¹, Wengang Wang¹, and George B. Richerson^{1, 2}

¹ Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06520-8018, and ² Veterans' Affairs Medical Center, West Haven, Connecticut 06516

The GABA transporter can reverse with depolarization, causing nonvesicular GABA release. However, this is thought to occur only under pathological conditions. Patch-clamp recordings were made from rat hippocampal neurons in primary cell cultures. Inhibition of GABA transaminase with the anticonvulsant -vinyl GABA (vigabatrin; 0.05-100 µM) resulted in a large leak current that was blocked by bicuculline (50 µM). This leak current occurred in the absence of extracellular calcium and was blocked by the GABA transporter antagonist SKF-89976a (5 µM). These results indicate that vigabatrin induces spontaneous GABA efflux from neighboring cells via reversal of GABA transporters, subsequently leading to the stimulation of GABA_A receptors on the recorded neuron. The leak current increased slowly over 4 d of treatment with 100 µM vigabatrin, at which time it reached an equivalent conductance of 9.0 ± 4.9 nS. Blockade of glutamic acid decarboxylase with semicarbazide (2 mM) decreased the leak current that was induced by vigabatrin by 47%. In untreated cells, carrier-mediated GABA efflux did not occur spontaneously but was induced by an increase in [K⁺]_o from 3 to as little as 6 mM. Vigabatrin enhanced this depolarization-evoked nonvesicular GABA release and also enhanced the heteroexchange release of GABA induced by nipecotate. Thus, the GABA transporter normally operates near its equilibrium and can be easily induced to reverse by an increase in cytosolic [GABA] or mild depolarization. We propose that this transporter-mediated nonvesicular GABA release plays an important role in neuronal inhibition under both physiological and pathophysiological conditions and is the target of some anticonvulsants.

Key words: seizure; epilepsy; vigabatrin; synapse; nonvesicular; hippocampus

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Copyright © 2001 Society for Neuroscience  0270-6474/01/2182630-10$05.00/0

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