New Molecular Mechanism Offers Hope For Treating Depression In The Elderly

Major depressive upset (MDD) is 1 of nan astir communal psychiatric illnesses worldwide, but its molecular causes have still not been intelligibly identified. A home investigation squad has discovered that slump whitethorn not simply beryllium caused by neuronal damage, but tin besides originate from nan dysregulation of circumstantial neural signaling pathways. In particular, they identified nan molecular logic why aged patients pinch slump do not respond to accepted antidepressants. This study suggests nan anticipation of therapeutic approaches utilizing optogenetic exertion to modulate neural signaling, and it provides clues for nan improvement of caller curen strategies targeting nan macromolecule 'Numb' macromolecule for aged patients pinch depression.

KAIST (President Kwang Hyung Lee) announced connected nan 19th of August that a investigation squad led by Distinguished Professor Won Do Heo of nan Department of Biological Sciences astatine KAIST, successful collaboration pinch forensic pathologist Minju Lee of nan National Forensic Service (Director Bong Woo Lee) and Professor Seokhwi Kim of nan Department of Pathology astatine Ajou University Medical Center (Director Sangwook Han), identified a caller molecular system for slump done RNA sequencing and nan immunohistochemical study of encephalon insubstantial from patients who had committed suicide. Furthermore, they demonstrated successful animal models that antidepressant effects tin beryllium restored by regulating nan signaling pathway that induces neural betterment utilizing optogenetic technology.

The investigation squad focused connected nan hippocampus, nan encephalon region responsible for representation and emotion, and successful peculiar connected nan dentate gyrus (DG). The DG is nan introduction constituent of accusation into nan hippocampus, playing a domiciled successful caller representation formation, neurogenesis, and affectional regulation, and is intimately linked pinch depression.

Using 2 typical rodent models for slump (the corticosterone accent exemplary and nan chronic unpredictable accent model), nan squad recovered that accent induced a striking summation successful nan signaling receptor FGFR1 (Fibroblast Growth Factor Receptor 1) successful nan DG. FGFR1 receives maturation facet (FGF) signals and transmits maturation and differentiation commands wrong cells.

Subsequently, utilizing conditional knockout (cKO) mice successful which nan FGFR1 cistron was deleted, nan researchers revealed that nan absence of FGFR1 made mice much susceptible to accent and led them to grounds depressive symptoms much quickly. This indicates that FGFR1 plays a captious domiciled successful due neural regularisation and accent resistance.

The squad past developed an 'optoFGFR1 system' utilizing optogenetics, enabling FGFR1 —essential for accent resistance—to beryllium activated by light. They observed that activating FGFR1 successful slump rodent models lacking FGFR1 restored antidepressant effects. In different words, they experimentally demonstrated that nan activation of FGFR1 signaling unsocial could amended depressive behavior.

Surprisingly, however, successful aged slump rodent models, nan activation of FGFR1 signaling done nan optoFGFR1 strategy did not output antidepressant effects. Investigating further, nan researchers recovered that successful nan aged brains, a macromolecule called 'Numb' was excessively expressed and interfered pinch FGFR1 signaling.

Indeed, study of postmortem quality encephalon insubstantial besides showed nan circumstantial overexpression of Numb macromolecule only successful aged patients pinch depression. When nan researchers suppressed Numb utilizing a cistron regulatory instrumentality (shRNA) while simultaneously activating FGFR1 signaling successful rodent models, neurogenesis and behavior—previously unrecoverable—returned to normal moreover successful aged slump models. This shows that nan Numb macromolecule acts arsenic a "blocker" of FGFR1 signaling and is simply a cardinal facet preventing nan hippocampus from executing antidepressant mechanisms.

This study is meaningful successful that it revealed that slump whitethorn not only consequence from elemental neuronal damage, but tin besides originate from nan dysregulation of circumstantial neural signaling pathways. In particular, we identified nan molecular logic why antidepressants are little effective successful aged patients, and we expect this to supply a hint for nan improvement of caller therapeutic strategies targeting nan Numb protein."

Won Do Heo, Distinguished Professor of KAIST

He added, "Moreover, this interdisciplinary study, which mixed KAIST's expertise successful neuroscience pinch nan National Forensic Service's forensic encephalon study technologies, is expected to service arsenic a span betwixt basal investigation connected psychiatric disorders and objective applications."

This study, led by first writer Jongpil Shin, a PhD student successful nan Department of Biological Sciences astatine KAIST, was published connected August 15, 2025, successful nan world diary Experimental & Molecular Medicine.