GABA-independent GABAA receptor openings maintain tonic currents

Activation of GABA receptors (GABARs) produces two forms of inhibition: phasic inhibition generated by the rapid, transient activation of synaptic GABARs by presynaptic GABA release, and tonic inhibition generated by the persistent activation of perisynaptic or extrasynaptic GABARs, which can detect extracellular GABA. Such tonic GABAR-mediated currents are particularly evident in dentate granule cells in which they play a major role in regulating cell excitability. Here we show that in rat dentate granule cells in ex vivo hippocampal slices, tonic currents are predominantly generated by GABA-independent GABA receptor openings. This tonic GABAR conductance is resistant to the competitive GABAR antagonist SR95531 (gabazine), which at high concentrations acts as a partial agonist, but can be blocked by an open channel blocker, picrotoxin. When slices are perfused with 200 nm GABA, a concentration that is comparable to CSF concentrations but is twice that measured by us in the hippocampus in vivo using zero-net-flux microdialysis, negligible GABA is detected by dentate granule cells. Spontaneously opening GABARs, therefore, maintain dentate granule cell tonic currents in the face of low extracellular GABA concentrations.