Major depressive disorder (MDD) is one of the most prevalent and debilitating mental health conditions, affecting millions worldwide. Recent evidence highlights the significance of circular RNAs (circRNAs) in the pathophysiological mechanisms underlying MDD.
In a recent study published in Genes & Diseases , researchers from Southeast University, Anhui Medical University and Chinese Academy of Sciences uncover how protein-encoding circRNAs contribute to MDD pathogenesis. Building on previous findings that circFKBP8(5S,6) and its encoded protein, cFKBP8, promote susceptibility to chronic unpredictable mild stress (CUMS) in mice, this study aimed to identify the specific molecular mechanisms linking circFKBP8/cFKBP8 to stress-related depressive behaviors using a model animal of depression.
Using RNA sequencing of prelimbic cortex (PrL) tissue from mice exposed to CUMS, researchers found that overexpression of circFKBP8(5S,6) or cFKBP8 significantly altered transcriptional profiles, with 520 differentially expressed genes (DEGs) in the circFKBP8 group and 537 DEGs in the cFKBP8 group. Gene Ontology (GO) and KEGG pathway enrichment analyses revealed that both groups converged on the neuroactive ligand–receptor interaction pathway, with dopamine receptor D3 (DRD3) emerging as a key down-regulated gene.
Further experiments confirmed that overexpression of circFKBP8(5S,6) or cFKBP8 suppressed DRD3 expression and disrupted AMPK/mTOR/ULK1 autophagy signaling, resulting in reduced neuronal autophagy in CUMS mice. Importantly, behavioral studies demonstrated that circFKBP8(5S,6) or cFKBP8 overexpression aggravated depressive-like phenotypes in stressed mice, including reduced sucrose preference and increased immobility in tail suspension and forced swim tests.
Interestingly, the DRD3 agonist cariprazine ameliorated severe depression-like behavior induced by circFKBP8(5S,6) or cFKBP8 in mice, and activated the AMPK/mTOR/ULK1 signaling pathway to up-regulate autophagy levels. Similarly, recombinant adeno-associated virus-mediated overexpression of DRD3 in PrL neurons improved depressive-like behaviors and reversed autophagy suppression induced by circFKBP8(5S,6) or cFKBP8.
In summary, this study reveals that circFKBP8(5S,6) or cFKBP8 promote susceptibility to CUMS in mice, at least in part, by down-regulating DRD3 expression and its downstream AMPK/mTOR/ULK1 signaling pathway-mediated neuronal autophagy. These findings provide new insights into the molecular mechanisms of MDD and point towards promising therapeutic targets.
Reference
Title of Original Paper: circFKBP8(5S,6)-encoded protein promotes stress susceptibility in mice by down-regulating dopamine D3 receptor expression and its downstream AMPK/mTOR/ULK1 autophagy signaling
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101718
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