Tiny sugars in the brain disrupt emotional circuits, fueling depression

Depression is a serious disorder that disrupts daily life through lethargy, sleep disturbance, and social withdrawal, and also increases the risk of suicide. The number of depression patients has steadily increased over the years, affecting more than 280 million people worldwide as of 2025. Now, researchers have uncovered a new pathological mechanism that could provide clues for the diagnosis and treatment of depression.

A research team led by C. Justin Lee and Lee Boyoung at the Institute for Basic Science (IBS) has identified a new molecular pathway in the brain that directly links abnormal sugar modifications in proteins to depressive behaviors. Specifically, chronic stress disrupts sugar chains (O-glycans) attached to proteins in the prefrontal cortex, thereby triggering depression.

The findings, published in Science Advances, open new possibilities for targeted therapies for treatment-resistant depression.

Depression arises from a complex interplay of psychological, environmental, and genetic factors, and many different pathological mechanisms have been reported. However, most antidepressant drugs in clinical use focus on regulating neurotransmitters, especially serotonin.

These drugs, however, benefit only about half of patients and often cause side effects such as gastrointestinal problems or worsening anxiety. This limitation underscores the need to search for new molecular pathways in the brain beyond neurotransmitter signaling.

The researchers focused on glycosylation, the process by which small sugar chains attach to proteins and alter their structure and function. Glycosylation has been recognized as an important mechanism in various diseases, including cancer, viral infections, and neurodegenerative disorders. Among its forms, O-glycosylation plays a role in cell signaling and maintaining balance in neural circuits, though its involvement in brain disorders has only recently begun to be studied.

Using high-performance mass spectrometry, the team first analyzed O-glycosylation patterns in nine brain regions of healthy mice and found that each region exhibited distinct glycosylation features. They then compared these with the brains of chronically stressed mice, revealing significant alterations in O-glycosylation in regions such as the prefrontal cortex.

In particular, they observed a reduction in sialylation—the addition of sialic acid to the ends of sugar chains, which stabilizes proteins—along with decreased expression of the enzyme St3gal1, which mediates this modification.

To test whether this enzyme is directly linked to depressive behavior, the researchers manipulated St3gal1 expression in the prefrontal cortex of both normal and stressed mice. Suppressing St3gal1 in normal mice caused them to exhibit depressive-like symptoms—loss of motivation, heightened anxiety—even without stress. Conversely, increasing St3gal1 in stressed mice alleviated their depressive behaviors. These results identify decreased St3gal1 as a key molecular factor that directly induces and regulates depressive symptoms.

Further protein analyses and electrophysiological experiments showed that reduced St3gal1 destabilized the sugar chain structures of synaptic molecules, including neurexin 2 (NRXN2), a synaptic adhesion protein, and impaired the function of inhibitory neurons that normally help maintain balance in brain circuits. In other words, small changes in sugar chains simultaneously disrupted both the connections and stability of neural circuits, ultimately collapsing the brain’s emotion-regulation system.

“This study demonstrates that abnormal glycosylation in the brain is directly connected to the onset of depression,” said Research 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.”