KAIST team uncovers neural signaling pathway behind depression in older adults

A team of researchers in Korea has discovered that depression can be caused by disruptions in specific neural signaling pathways. In particular, they have identified the molecular mechanisms underlying the reduced efficacy of existing antidepressants in elderly patients.

The Korea Advanced Institute of Science and Technology (KAIST) announced on Tuesday that a research team led by Chair Professor Heo Won-do of the Department of Biological Sciences has published these findings. Professor Heo collaborated with Dr. Lee Min-ju of the National Forensic Service (NFS) and Professor Kim Seok-hwi of the Department of Pathology at Ajou University Hospital.

The research team focused on the dentate gyrus, a region of the hippocampus responsible for memory and emotion, particularly its role in forming new memories and regulating emotions. Animal experiments revealed that when exposed to stress, the protein FGFR1 increases in this area, playing a role in protecting neural function.

Mice lacking FGFR1 were more susceptible to stress and exhibited depressive symptoms more rapidly. When FGFR1 was artificially activated using light, depressive symptoms decreased, and antidepressant effects were restored.

However, activating FGFR1 had no effect in aged mice. The research team discovered that the reason was the protein “Numb.” This protein was overproduced, blocking the action of FGFR1. The same phenomenon was confirmed in brain tissue from elderly patients with depression.

When the research team reduced Numb while simultaneously activating FGFR1, neural function and behavior returned to normal even in older mice. This suggests that the Numb protein could be a new target for treating elderly depression.

“This study is significant in that it reveals that depression may arise not only from simple neuronal damage but also from disruptions in specific neural signaling pathways,” Professor Heo said. “We anticipate that this interdisciplinary research, which combines KAIST’s expertise in neuroscience with the National Forensic Service’s forensic-based brain analysis technology, will serve as a bridge between basic research on mental disorders and clinical applications in the future.”

The study, in which Shin Jong-pil, a doctoral candidate in KAIST's Department of Biological Sciences, served as the first author, was published last Friday in the international academic journal, Experimental & Molecular Medicine, under the title “Dysregulation of the FGFR1 signaling in hippocampus facilitates depressive disorder.”