ULK1 inhibits depressive behaviours by reversing RYR2-mediated hyperactivity in lateral habenula

Brain. 2026 Sep 9:awag298. doi: 10.1093/brain/awag298. Online ahead of print.

ABSTRACT

Research has implicated disrupted autophagy initiation in the pathophysiology of depression. However, the role of Unc-51-like Kinase 1 (ULK1), a key regulator of autophagy initiation, in depression remains poorly understood. Here, using behavioural, molecular, and genetic approaches, we show that serum ULK1 levels are decreased in both patients with depression and mice susceptible to chronic social-defeat stress, and that both ULK1 and p-ULK1 (Ser-555) are downregulated in the lateral habenula (LHb) of susceptible mice. In addition, ULK1 deficiency in the LHb is sufficient to induce depressive-like behaviours in mice. Conversely, restoration of ULK1 in the LHb, either genetically or pharmacologically, produced antidepressant-like effects. Moreover, ULK1 deficiency specifically in LHb glutamatergic neurons induces neuronal hyperactivity, which contributes to ULK1 deficiency-induced depressive-like behaviours. Mechanistically, LHb glutamatergic neuron-specific ULK1 deficiency upregulates ryanodine receptor 2 (RYR2), which mediates increased stress-evoked presynaptic calcium transients, enhances presynaptic glutamatergic transmission, and neuronal hyperactivity in the LHb, ultimately resulting in depressive-like behaviours. Collectively, our findings suggest that ULK1 deficiency in LHb glutamatergic neurons may contribute to the development and progression of depression and identify ULK1 as a potential target for further investigation in antidepressant therapy development.

PMID:42714059 | DOI:10.1093/brain/awag298