– KAIST-National Forensic Service-Ajou University Joint Research
– New Treatment Proposed for Elderly Depression Patients
[Herald Economics = Koo Bonhyeok, Reporter]: A domestic research team has discovered that depression may not merely be due to nerve cell damage but might also arise from disturbances in specific neural signaling pathways. Furthermore, the research identified molecular causes for why existing antidepressants might not work for elderly depression patients.
On the 19th, KAIST announced that the research team led by Distinguished Professor Huh Won-do from the Department of Biological Sciences at KAIST, in collaboration with Min-ju Lee, a Legal Medicine Specialist at the National Forensic Service, and Professor Kim Seok-hwi from Ajou University, has unveiled new molecular mechanisms of depression through RNA base sequencing and immunohistochemical analysis of brain tissues from patients who have taken their own lives. They demonstrated that by regulating signaling pathways that induce neural recovery via optogenetics technology, antidepressant effects can be restored.
The research team focused on the hippocampus, a brain region responsible for memory and emotions, particularly the ‘dentate gyrus (DG).’ The dentate gyrus is the area where information first enters the hippocampus, creating new memories, allowing neural growth, and playing a role in emotional regulation associated with depression.
Utilizing two representative mouse models of depression, the research found that during stress, the signaling receptor known as FGFR1, which accepts the signaling molecule growth factor (FGF) facilitating cell growth and differentiation within cells, significantly increased in the DG area.
Subsequent experiments with ‘conditional knockout (cKO) mice,’ which had the FGFR1 gene conditionally removed, revealed that these mice were more susceptible to stress and displayed depressive symptoms more rapidly.
The research team developed the ‘optoFGFR1 system,’ which can activate FGFR1, crucial for stress resistance, using light through optogenetics technology. In depression mouse models lacking FGFR1, they observed that activating this system could recover antidepressant effects, experimentally demonstrating that merely activating FGFR1 signaling could improve depressive behaviors.
However, surprisingly, in aged depression mouse models, the activation of FGFR1 signaling through the ‘optoFGFR1 system’ did not yield antidepressant effects. Investigating further, the research team discovered that the protein ‘Numb’ was excessively expressed in the aged brain, hindering FGFR1 signaling.
By expressing a gene regulation tool (shRNA) that inhibits Numb in the mouse model and simultaneously activating FGFR1 signaling, researchers could restore normal neurogenesis and behavior in aged depression mouse models that previously showed no recovery.
Distinguished Professor Huh Won-do stated, “This research is significant as it reveals that depression can arise not only from simple nerve cell damage but also through disturbances in specific neural signaling pathways.” He added, “By elucidating the molecular reasons why antidepressants may not be effective in elderly patients, we provide a basis for developing new treatments targeting the Numb protein in the future.”
These research findings were published in the international journal ‘Experimental & Molecular Medicine’ on August 15th.