A mouse mannequin displaying depression-like behaviors was established by exposing animals to continual variable stress (left). A multi-omics method was then utilized, utilizing high-resolution mass spectrometry to research O-glycan composition and protein alterations throughout 9 distinct mind areas (middle). This evaluation revealed a pronounced discount in sialylation and downregulation of the glycosyltransferase St3gal1 within the prefrontal cortex, along with related adjustments in synaptic proteins and inhibitory neuronal operate (proper). By this built-in technique, the research demonstrated a direct hyperlink between mind O-glycosylation abnormalities and depression-like behaviors. Credit score: Institute for Fundamental Science
Melancholy is a critical dysfunction that disrupts every day life by lethargy, sleep disturbance, and social withdrawal, and in addition will increase the danger of suicide. The variety of despair sufferers has steadily elevated through the years, affecting greater than 280 million individuals worldwide as of 2025. Now, researchers have uncovered a brand new pathological mechanism that might present clues for the analysis and therapy of despair.
A analysis group led by C. Justin Lee and Lee Boyoung on the Institute for Fundamental Science (IBS) has recognized a brand new molecular pathway within the mind that straight hyperlinks irregular sugar modifications in proteins to depressive behaviors. Particularly, continual stress disrupts sugar chains (O-glycans) connected to proteins within the prefrontal cortex, thereby triggering despair.
The findings, printed in Science Advances, open new potentialities for focused therapies for treatment-resistant despair.
Melancholy arises from a fancy interaction of psychological, environmental, and genetic elements, and many alternative pathological mechanisms have been reported. Nevertheless, most antidepressant medication in medical use concentrate on regulating neurotransmitters, particularly serotonin.
These medication, nevertheless, profit solely about half of sufferers and sometimes trigger negative effects corresponding to gastrointestinal issues or worsening nervousness. This limitation underscores the necessity to seek for new molecular pathways within the mind past neurotransmitter signaling.
O-glycan expression patterns had been in contrast throughout 9 mind areas in management (CON) and continual variable stress (CVS) mice (left). Area-specific glycosylation profiles had been noticed all through the mind, with stress-induced adjustments most pronounced within the prefrontal cortex (PFC), cerebellar cortex (CC), olfactory bulb (OLB), and diencephalon (DIE) (proper). These findings point out that continual stress disrupts O-glycosylation, notably O-glycan sialylation, in particular mind areas, doubtlessly contributing to depression-like behaviors. Credit score: Institute for Fundamental Science
The researchers centered on glycosylation, the method by which small sugar chains connect to proteins and alter their construction and performance. Glycosylation has been acknowledged as an essential mechanism in numerous illnesses, together with most cancers, viral infections, and neurodegenerative problems. Amongst its kinds, O-glycosylation performs a task in cell signaling and sustaining steadiness in neural circuits, although its involvement in mind problems has solely lately begun to be studied.
Utilizing high-performance mass spectrometry, the group first analyzed O-glycosylation patterns in 9 mind areas of wholesome mice and located that every area exhibited distinct glycosylation options. They then in contrast these with the brains of chronically pressured mice, revealing vital alterations in O-glycosylation in areas such because the prefrontal cortex.
Specifically, they noticed a discount in sialylation—the addition of sialic acid to the ends of sugar chains, which stabilizes proteins—together with decreased expression of the enzyme St3gal1, which mediates this modification.
To check whether or not this enzyme is straight linked to depressive habits, the researchers manipulated St3gal1 expression within the prefrontal cortex of each regular and pressured mice. Suppressing St3gal1 in regular mice brought about them to exhibit depressive-like signs—lack of motivation, heightened nervousness—even with out stress. Conversely, growing St3gal1 in pressured mice alleviated their depressive behaviors. These outcomes establish decreased St3gal1 as a key molecular issue that straight induces and regulates depressive signs.
Injection of a virus suppressing St3gal1 expression (shSt3gal1) into the prefrontal cortex of regular mice induced depression-like behaviors. These mice exhibited elevated latency to feed in a novel surroundings, reflecting heightened nervousness and lowered feeding motivation (NSFT, novelty-suppressed feeding take a look at), in addition to decreased sucrose choice, indicating anhedonia (SPT, sucrose choice take a look at). Credit score: Institute for Fundamental Science
Injection of a virus enhancing St3gal1 expression (St3gal1-GFP) into the medial prefrontal cortex (mPFC) of mice uncovered to continual variable stress (CVS) markedly alleviated depression-like behaviors. Pressured mice expressing GFP alone (CVS.GFP) confirmed extended latency to feed in a novel surroundings, indicating heightened nervousness and lowered feeding motivation (NSFT), in addition to elevated immobility, reflecting despair-like habits or passive stress-coping habits (TST). In distinction, mice with restored St3gal1 expression (CVS.St3gal1-GFP) exhibited vital behavioral enchancment. These findings recommend that restoration of St3gal1 expression within the mPFC can mitigate depression-related behaviors. Credit score: Institute for Fundamental Science
Additional protein analyses and electrophysiological experiments confirmed that lowered St3gal1 destabilized the sugar chain buildings of synaptic molecules, together with neurexin 2 (NRXN2), a synaptic adhesion protein, and impaired the operate of inhibitory neurons that usually assist keep steadiness in mind circuits. In different phrases, small adjustments in sugar chains concurrently disrupted each the connections and stability of neural circuits, finally collapsing the mind’s emotion-regulation system.
“This study demonstrates that abnormal glycosylation in the brain is directly connected to the onset of depression,” mentioned Analysis Fellow Boyoung Lee. “It provides an important foothold for identifying new diagnostic markers and therapeutic targets beyond neurotransmitters.”
“Depression imposes a major social burden, yet current treatments remain limited,” added Director C. Justin Lee. “This achievement could extend not only to depression therapy but also to other mental illnesses such as PTSD and schizophrenia, paving the way for broader therapeutic strategies.”
Extra info:
Youngsuk Search engine marketing et al, Irregular O-Glycan Sialylation within the mPFC Contributes to Depressive-like Behaviors in Male Mice, Science Advances (2025). DOI: 10.1126/sciadv.ady2733.
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