Targeting autophagy in lateral habenula for alleviating depression

Depression affects over 300 million people worldwide and is a leading cause of disability. Current treatments have limited efficacy in achieving remission and require several weeks to months of therapy for lessening depressive symptoms. Reduced autophagy is commonly observed in the brain of individuals with major depressive disorder, impairing cellular homeostasis and synaptic plasticity, the processes vital for mood regulation. A recent study published in the journal Nature reported that a key driver for depression in a mouse model of acute and chronic stress is an impaired autophagy in the lateral habenula, a brain region known to regulate motivation, reward, and aversion. Notably, direct infusion of beclin-1 peptide into this region rapidly restored autophagy markers and reduced depressive symptoms, highlighting a fast-acting mechanism distinct from the way conventional antidepressants act. Such effects were attributed to reduced excitatory neurotransmitter receptors, which could ease neuronal hyperactivity without affecting inhibitory neurotransmission, demonstrating that the selective autophagic degradation of excitatory receptors in the lateral habenula can mediate antidepressant effects. However, several issues remain to be addressed, including the long-term efficacy and the feasibility of the approach for clinical translation. This review critically discusses the proficiency, limitations, and clinical translatability of the lateral habenula autophagy enhancement approach. The promise of other autophagy enhancers and the possibility of combinational therapy, where drugs or dietary supplements could enhance autophagy, diminish neuroinflammation, and regulate neurotransmitters, is also discussed.