Epilepsy and GABA

Neurosciences Journal Club

Ogan Gurel, CC4 5 October 1995

During MJ, Ryder KM and Spencer DD, “Hippocampal GABA transporter function in temporal-lobe epilepsy,” Nature, Vol 376, 13 July 1995, pp. 174-177.

Summary

Studied in vivo extracellular GABA levels in hippocampi from temporal lobe epilepsy patients as well as in amygdala-kindled rats. Eight patients were studied using implanted microdialysis probes to inject potassium, calcium and glutamate and analyze the effects on extracellular GABA levels. Likewise, amygdala-kindled rats (an animal-model of human epilepsy) were similarly studied; additionally, in the rat experiments injections of the specific GABA-transporter inhibitor nipecotic acid were also assessed both in terms of effects on GABA levels as well as in quantitating the numbers of GABA transporters.

Fig 1

GABA release in the human hippocampus Used microdialysis to study the two types of GABA release: local and generalized. Epileptogenic hippocampi showed a relative increase in K+ stimulated, local, vesicular GABA release but showed a relative decrease in glutamate stimulated, generalized, transport-mediated GABA release. Comment Numbers are low, but pvalues significant. Technically speaking, microdialysis technically only analyzes free extracellular GABA and may not be representative of levels within the synaptic cleft.

Fig 2

GABA release in the rat hippocampus Figure b shows the same results in rats. In addition, the GABA-transporter inhibitor nipecotic acid abolished the glutamate-mediated increase in extracellular GABA arguing that GABA transport is involved in generalized GABA release. Comment It would have been interesting to study the effects on nipecotic acid on the potassiummediated release.

Table 1

Scatchard analysis shows an unchanged Kd but a decreased Bmax in amygdala kindled rats arguing for a quantitative reduction (non-competitive inhibition model) in the number GABA transporters in “epileptic” rats. Comment Intact rat hippocampus, assessment of nonspecific binding, and careful analysis make this an intriguing and useful result.

3H-Nipecotic acid binding in rat hippocampus

Conclusion

Epileptogenic hippocampi have a decreased number of GABA transporters which results in a decreased generalized non-vesicular release of the inhibitory neurotransmitter GABA.

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