Synaptic properties of GABA co-releasing synapses in the lateral habenula

The lateral habenula (LHb) is a key epithalamic structure involved in the regulation of mood, motivation, and reward processing. Acting as a hub between forebrain regions and midbrain monoaminergic centers, its dysfunction has been linked to disorders such as depression and addiction. Understanding the synaptic architecture and neurotransmitter dynamics within the LHb is therefore essential for elucidating its role in brain function and pathology. In this study, we characterized the synaptic properties of GABA co-releasing synapses within the LHb. Whole-cell voltage-clamp recordings were performed in transgenic mice expressing channelrhodopsin-2 (ChR2) in glutamatergic neurons. Optogenetic stimulation allowed selective activation of these inputs while pharmacologically isolating GABAergic currents. We examined the contribution of presynaptic calcium channels to GABA co-release by pharmacologically blocking P/Q-type and N-type calcium channels. Our findings indicate that both channel types support GABA co-release in the LHb, with P/Q-type channels playing a predominant role. The differential contribution of calcium channels to GABA co-release may influence the excitatory-inhibitory balance of habenular output, thereby modulating downstream monoaminergic systems implicated in mood and reward. Understanding these mechanisms could provide new insights into the synaptic basis of neuropsychiatric disorders and highlight potential therapeutic targets for neuropsychiatric disorders.