GABA(A) autoreceptors enhance GABA release from human neocortex: towards a mechanism for high-frequency stimulation (HFS) in brain?

High-frequency stimulation (HFS) in human neocortical slices induces gamma-aminobutyric acid (GABA) release via GABA(A) receptor (GABA(A)R) activation. The mechanism of this effect and the localization of these GABA(A)Rs were now studied. Fresh human neocortical slices were subjected to HFS (130 Hz) in the presence of veratridine (3 microM). As measured by high-performance liquid chromatography, only GABA but not glutamate outflow was affected by HFS/veratridine stimulation. The evoked GABA overflow was abolished by tetrodotoxin and furosemide, suggesting an involvement of action potentials and plasmalemmal chloride gradients. Double immunolabeling showed that GABA(A)Rs are localized on soma and dendrites of GABAergic neurons in the human neocortex. Moreover, in support of a terminal localization of GABA(A)Rs, the K+-evoked [3H]-GABA release from synaptosomes was enhanced by the GABA(A)R agonist muscimol (antagonized by GABA(A)R blockers). We conclude that HFS in human brain neocortex leads to a specific increase of GABA release, which is mediated by facilitatory GABA(A) autoreceptors located on soma, dendrites, and axon terminals of GABAergic neurons.