A groundbreaking study by South Korean researchers has uncovered a molecular mechanism that could explain why depression in elderly patients often resists conventional antidepressants, offering new avenues for treatment.
Major depressive disorder (MDD) affects millions worldwide, yet its underlying molecular causes have remained largely elusive. Researchers from KAIST, in collaboration with the National Forensic Service and Ajou University Medical Center, have found that depression may stem not only from neuronal damage but also from disruptions in specific neural signaling pathways. Their findings suggest that targeting the protein ‘Numb’ could restore antidepressant efficacy in older adults.
The research team, led by Distinguished Professor Won Do Heo of KAIST’s Department of Biological Sciences, analyzed postmortem brain tissue from individuals who had committed suicide, using RNA sequencing and immunohistochemical methods. In parallel, animal experiments demonstrated that activating certain neural signaling pathways with optogenetic technology could reverse depressive behaviors.
Focusing on the hippocampus, particularly the dentate gyrus (DG)—a key region for memory, emotion, and neurogenesis—the team discovered that stress triggers a significant increase in the signaling receptor FGFR1 (Fibroblast Growth Factor Receptor 1). FGFR1 mediates growth and differentiation within neurons, playing a critical role in stress resilience.
Using genetically modified mice lacking FGFR1, researchers observed heightened vulnerability to stress and accelerated depressive behaviors, confirming the receptor’s importance in neural regulation. To restore its function, the team developed an “optoFGFR1 system,” which activates FGFR1 with light. Activation in depressed mice successfully reversed depressive symptoms.
However, the approach initially failed in aged depression models. Further investigation revealed that excessive expression of the Numb protein in older brains blocked FGFR1 signaling. When the researchers suppressed Numb using gene regulation tools while activating FGFR1, both neurogenesis and behavioral deficits were restored, even in aged mice. Postmortem human brain analysis confirmed that Numb overexpression occurs specifically in elderly patients with depression.
“This discovery explains why conventional antidepressants are often less effective in older adults and points to new therapeutic strategies targeting the Numb protein,” said Professor Heo. He highlighted that the study bridges basic neuroscience research and clinical applications, leveraging KAIST’s expertise in neural biology and the National Forensic Service’s forensic brain analysis techniques.
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