Lateral habenula dysfunction in depression: Mechanisms and therapeutic prospects

Emerging evidence implicates lateral habenula (LHb) hyperactivity—as it persistently inhibits midbrain dopamine and serotonin systems—in major depressive disorder (MDD). LHb neurons co‑release glutamate and GABA to encode aversive and reward‑omission signals; depression is marked by increased glutamate release, reduced GABA inhibition, CaMKIIβ/PP2A‑driven synaptic plasticity changes, and astrocytic Kir4.1 overexpression, all promoting pathological burst firing. Targeting these mechanisms in animal models—via Kir4.1 blockade, optogenetic or chemo genetic modulation, and NMDA receptor antagonism—produces rapid antidepressant effects. Clinically, preliminary deep brain stimulation of the LHb significantly improves symptoms in treatment‑resistant depression. Future research should optimize cell‑type– specific interventions, refine neuromodulation parameters, and validate long‑term safety and efficacy in large trials, paving the way for precise, effective LHb‑targeted therapies for MDD. This review summarizes the key role of LHb dysfunction in depression pathogenesis and highlights recent advances toward translating LHb‑based interventions into clinical practice.