Optogenetic activation of septal GABAergic afferents entrains neuronal firing in the medial habenula

The medial habenula (MHb) plays an important role in nicotine-related behaviors such as nicotine aversion and withdrawal. The MHb receives GABAergic input from the medial septum/diagonal band of Broca (MS/DB), yet the synaptic mechanism that regulates MHb activity is unclear. GABA (gamma-aminobutyric acid) is a major inhibitory neurotransmitter activating both GABA(A) receptors and GABA(B) receptors. Depending on intracellular chloride concentration, however, GABA(A) receptors also function in an excitatory manner. In the absence of various synaptic inputs, we found that MHb neurons displayed spontaneous tonic firing at a rate of about similar to 4.4 Hz. Optogenetic stimulation of MS/DB inputs to the MHb evoked GABA(A) receptor-mediated synaptic currents, which produced stimulus-locked neuronal firing. Subsequent delayed yet lasting activation of GABA(B) receptors attenuated the intrinsic tonic firing. Consequently, septal GABAergic input alone orchestrates both excitatory GABA(A) and inhibitory GABA(B) receptors, thereby entraining the firing of MHb neurons.