Role of the GABA Transporter in Epilepsy
The GABA transporter plays a well-established role in reuptake of GABA after synaptic release. The anticonvulsant effect of tiagabine appears to result largely from blocking this reuptake. However, there is another side to the GABA transporter, contributing to GABA release by reversing in response to depolarization. We have recently shown that this form of GABA release is induced by even small increases in extracellular [K+], and has a powerful inhibitory effect on surrounding neurons. This transporter-mediated GABA release is enhanced by the anticonvulsants gabapentin and vigabatrin. The latter drug also potently increases ambient [GABA], inducing tonic inhibition of neurons. Here we review the evidence in support of a physiological role for GABA transporter reversal, and the evidence that it is increased by high-frequency firing. We postulate that the GABA transporter is a major determinant of the level of tonic inhibition, and an important source of GABA release during seizures. These recent findings indicate that the GABA transporter plays a much more dynamic role in control of brain excitability than has previously been recognized. Further defining this role may lead to a better understanding of the mechanisms of epilepsy and new avenues for treatment.
KeywordsGABAA Receptor Gaba Release Tonic Inhibition Tetanus Toxin Gaba Transporter
Unable to display preview. Download preview PDF.
- 19.Jung MJ, Palfreyman MG. Vigabatrin mechanisms of action. In: Levy RH, Mattson RH, Meldrum BS, eds. Antiepileptic drugs. New York: Raven Press, 1995: 903–913.Google Scholar
- 22.Lerma J, Herranz AS, Herreras O et al. In vivo determination of extracellular concentration of amino acids in the rat hippocampus. A method based on brain dialysis and computerized analysis. Brain Res 1986; 384: 145–155.Google Scholar
- 36.Petroff OA, Rothman DL, Behar KL et al. The effect of gabapentin on brain gamma-aminobutyric acid in patients with epilepsy. Ann Neurol 19966; 39: 95–99.Google Scholar
- 49.Stell BM, Mody I. Receptors with different affinities mediate phasic and tonic GABA(A) conductances in hippocampal neurons. J Neurosci 2002; 22:RC223.Google Scholar