Calcium-activated ion channels drive atypical inhibition in medial habenula neurons

Nicotine is an addictive substance that poses substantial health and societal challenges. Despite the known links between the medial habenula (MHb) and nicotine avoidance, the ionic mechanisms underlying MHb neuronal responses to nicotine remain unclear. Here, we report that MHb neurons use a long-lasting refractory period (LLRP) as an unconventional inhibitory mechanism to curb hyperexcitability. This process is initiated by nicotine-induced calcium influx through nicotinic acetylcholine receptors, which activates a calcium-activated chloride channel (CaCC). Owing to high intracellular chloride levels in MHb neurons, chloride efflux through CaCC, coupled with high-threshold voltage-gated calcium channels, sustains MHb depolarization near the chloride equilibrium potential of -30 millivolts, thereby enabling LLRP. Concurrently, calcium-activated BK potassium channels counteract this depolarization, promoting LLRP termination. Our findings reveal an atypical inhibitory mechanism, orchestrated by synergistic actions between calcium-permeable and calcium-activated channels. This discovery advances our understanding of neuronal excitability control and nicotine addiction.