Dual GABAergic Synaptic Response of Fast Excitation and Slow Inhibition in the Medial Habenula of Rat Epithalamus

We report here a novel action of GABAergic synapses in regulating tonic firing in the 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 at postnatal days 18–25 generates a combinatorial activation of fast excitation and slow inhibition. The fast excitation, mediated by γ-aminobutyric acid type A receptors (GABAARs), is alone capable of triggering robust action potentials to increase cell firing. This excitatory influence of 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 GABABRs 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 GABAARs and GABABRs generates distinct temporal patterns of cell firing that alter the cellular output in an activity-dependent manner.