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AsianScientist (Jan. 21, 2026) – Major depressive disorder (MDD) is a complex mental illness that affects mood and thinking in people of all ages. It stems from a mix of genetic, biological, and environmental factors, making it hard to treat. While it is one of the most common psychiatric disorders worldwide, the exact molecular mechanisms behind it are still not well understood.
Recently, researchers at the Korea Advanced Institute of Science and Technology (KAIST) discovered a new molecular pathway related to depression. They used RNA sequencing and immunohistochemical analysis on brain tissue samples from individuals who died by suicide.
They also showed in animal models that antidepressant effects could be restored by changing a signaling pathway that helps with neural recovery by using optogenetic technology to control cellular activity with light.
Their findings were published in the journal Experimental & Molecular Medicine.
The scientists focused on the hippocampus, a part of the brain that regulates memory and emotion, paying special attention to the dentate gyrus (DG). The DG is the entry point for information into the hippocampus and is crucial for forming new memories, generating neurons, and regulating emotions, all processes closely linked to depression.
Using two established mouse models of depression – the corticosterone stress model and the chronic unpredictable stress model, the researchers found that stress significantly increased the signaling receptor FGFR1 (Fibroblast Growth Factor Receptor 1) in the DG. FGFR1 receives signals from growth factors (FGFs) and directs cellular growth and differentiation.
To examine its role further, the team used conditional knockout (cKO) mice that lacked the FGFR1 gene. These mice were more susceptible to stress and showed depressive symptoms more quickly, suggesting that FGFR1 is vital for maintaining stability and resilience in neural systems.
The researchers then introduced an “optoFGFR1 system” using optogenetics, allowing them to activate FGFR1 with light. When they reactivated FGFR1 in depression-prone mice that lacked the receptor, they restored antidepressant effects. This finding showed that simply activating FGFR1 signaling could improve depressive behaviors.
However, in older mouse models of depression, activating FGFR1 signaling with the optoFGFR1 system did not produce antidepressant effects.
Further analysis revealed that a protein called Numb was overly expressed in aged brains, interfering with FGFR1 signaling.
Moreover, postmortem analysis of human brain tissue confirmed that Numb was specifically overexpressed in older patients with depression. When the researchers used a gene-silencing tool (shRNA) to reduce Numb while activating FGFR1 signaling in mice, neurogenesis and normal behaviors returned even in aged models.
These findings suggest that Numb acts as a “blocker” of FGFR1 signaling, stopping the hippocampus from triggering its natural antidepressant mechanisms and point to Numb as a potential new target for treating depression.
“This study is meaningful in that it revealed that depression may not only result from simple neuronal damage, but can also arise from the dysregulation of specific neural signaling pathways. In particular, we identified the molecular reason why antidepressants are less effective in elderly patients, and we expect this to provide a clue for the development of new therapeutic strategies targeting the Numb protein,” said Won Do Heo, Professor, Department of Biological Sciences, KAIST.
“Moreover, this interdisciplinary study, which combined KAIST’s expertise in neuroscience with the National Forensic Service’s forensic brain analysis technologies, is expected to serve as a bridge between basic research on psychiatric disorders and clinical applications,” he added.
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Source: KAIST (Korea Advanced Institute of Science and Technology); Image: Iammotos/Shutterstock
The study can be found at: Dysregulation of FGFR1 signaling in the hippocampus facilitates depressive disorder
Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.
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