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We report here a novel action of GABAergic synapses in regulating tonic firing in the mature mammalian brain. By using gramicidin-perforated patch recording in rat brain slices, we show that cells of the medial habenula of the epithalamus generate tonic firing in basal conditions. The GABAergic input onto these cells generates a combinatorial activation of fast excitation and slow inhibition. The fast excitation is mediated by GABAA receptors and alone capable of triggering robust action potentials to increase cell firing. This excitatory influence of the GABAergic input results from the Cl(- )homeostasis that maintains intracellular Cl(- )at high levels. The GABAA excitation is often followed by a slow inhibition mediated by GABAB receptors that suppresses tonic firing. Interestingly, in a subpopulation of the cells, the GABAB inhibition exhibits a remarkably low threshold for synaptic activation in that low-strength GABAergic input often activates selectively the GABAB slow inhibition, whereas the GABAA excitation requires further increases in stimulus strength. Our study demonstrates that the dual activation of GABAergic excitation and inhibition through GABAA and GABAB receptors generates distinct temporal patterns of cell firing that alter the cellular output in an activity-dependent manner.
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