Selective enhancement of tonic inhibition by increasing ambient GABA is insufficient to suppress excitotoxicity in hippocampal neurons

γ-Aminobutyric acid (GABA) activates synaptic GABA_A receptors to generate inhibitory postsynaptic potentials. GABA also acts on extrasynaptic GABA_A receptors, resulting in tonic inhibition. The physiological role of tonic inhibition, however, remains elusive. We explored the neurophysiological significance of tonic inhibition by testing whether selective activation of extrasynaptic GABA_A receptors is sufficient to curb excitotoxicity. Tonic inhibition was selectively enhanced by increasing ambient GABA. In both acute hippocampal slices and cultured hippocampal neurons, boosting tonic inhibition alone is insufficient to withstand the hyper-excitability of hippocampal neurons induced by low-magnesium (Mg ²⁺) baths. Furthermore, selective activation of extrasynaptic GABA_A receptors resulted in no significant neuroprotective effects against glutamate or low-Mg²⁺-induced neuronal cell deaths. These data imply that under physiological conditions extrasynaptic GABA_A receptors are optimally activated by ambient GABA and that a further increase in extracellular GABA concentration will not significantly enhance the effect of tonic inhibition on neuronal excitability.