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

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ID: 328258
2026
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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.
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openalex_W7211998365 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Pingjie Wang, Xiaohan Tong, Yun Liu, Junfeng Li, Shilin He, Yanhua Huang, Ruijia Ma, Boya Huang, Wenghei Hong, Ruizhe Sun, Nikias Siafarikas, Tormod Fladby, He-Ling Wang, Oscar Junhong Luo, Qian Wang, Yuchao Li, Ji‐chun Zhang, Lu Huang, Chaoran Ren, Guobing Chen, Evandro Fei Fang, Song Lin
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Journal Brain research
Year 2026
DOI
10.1093/brain/awag298
URL
https://doi.org/10.1093/brain/awag298
Keywords Keywords not found

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