New molecular mechanism found for depression

Major depressive disorder (MDD) is one of the most common psychiatric illnesses worldwide, but its molecular causes have still not been clearly identified. Now, researchers from the Korea Advanced Institute of Science and Technology (KAIST) have discovered that depression may not simply be caused by neuronal damage, with their work published in the journal Experimental & Molecular Medicine.

The research team focused on the hippocampus, the brain region responsible for memory and emotion, and in particular on the dentate gyrus (DG). The DG is the entry point of information into the hippocampus, playing a role in new memory formation, neurogenesis and emotional regulation, and is closely linked with depression.

Using two representative mouse models for depression (the corticosterone stress model and the chronic unpredictable stress model), the team found that stress induced a striking increase in the signalling receptor FGFR1 (fibroblast growth factor receptor 1) in the DG. FGFR1 receives growth factor (FGF) signals and transmits growth and differentiation commands within cells.

Subsequently, using conditional knockout (cKO) mice in which the FGFR1 gene was deleted, the researchers revealed that the absence of FGFR1 made mice more vulnerable to stress and led them to exhibit depressive symptoms more quickly. This indicates that FGFR1 plays a critical role in proper neural regulation and stress resistance.

The team then developed an ‘optoFGFR1 system’ using optogenetics, enabling FGFR1 — essential for stress resistance — to be activated by light. They observed that activating FGFR1 in depression mouse models lacking FGFR1 restored antidepressant effects. In other words, they experimentally demonstrated that the activation of FGFR1 signalling alone could improve depressive behaviour.

Surprisingly, however, in aged depression mouse models, the activation of FGFR1 signalling through the optoFGFR1 system did not yield antidepressant effects. Investigating further, the researchers found that in the aged brains, a protein called ‘Numb’ was excessively expressed and interfered with FGFR1 signalling.

Indeed, analysis of postmortem human brain tissue from patients who had died of suicide also showed the specific overexpression of Numb protein only in elderly patients with depression. When the researchers suppressed Numb using a gene regulatory tool (shRNA) while simultaneously activating FGFR1 signalling in mouse models, neurogenesis and behaviour — previously unrecoverable — returned to normal even in aged depression models. This shows that the Numb protein acts as a ‘blocker’ of FGFR1 signalling and is a key factor preventing the hippocampus from executing antidepressant mechanisms.

“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 signalling pathways,” said research team leader Distinguished Professor Won Do Heo. “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.

“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.”

Image credit: iStock.com/KatarzynaBialasiewicz