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 γ-aminobutyric acid (GABA) release via GABA_A receptor (GABA_AR) activation. The mechanism of this effect and the localization of these GABA_ARs were now studied. Fresh human neocortical slices were subjected to HFS (130 Hz) in the presence of veratridine (3 μM). 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_ARs are localized on soma and dendrites of GABAergic neurons in the human neocortex. Moreover, in support of a terminal localization of GABA_ARs, the K⁺-evoked [ ³H]-GABA release from synaptosomes was enhanced by the GABA _AR agonist muscimol (antagonized by GABA_AR 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.