Major Depression-Associated NEGR1 Gene is Modulated in Stress-Susceptible Male Mice

Background: Neuronal growth regulator 1 (NEGR1) is an IgLON cell adhesion molecule significantly associated with depression risk in genome-wide association studies. Since the role of NEGR1 in depression pathophysiology remains incompletely understood, we investigated changes in NEGR1-associated gene expression levels in stress-susceptible male mice exposed to chronic restraint stress. Methods: Mice were subjected to 21 consecutive days of restraint stress, and stress-induced maladaptive phenotypes were evaluated by tail suspension, forced swim, splash, and open field tests. After sacrifice, the hippocampi were collected, and the levels of NEGR1-associated genes were assessed by quantitative polymerase chain reaction (qPCR). Results: In the stress-exposed group, weight was significantly reduced, and immobility time was significantly higher in the tail suspension and the forced swim tests, while grooming bouts in the splash test were reduced. No changes were observed in the open field test. A z-score normalization integrating all behavioural parameters was applied to classify the animals as resilient or susceptible to restraint stress. In stress-susceptible mice, NEGR1, Fibroblast Growth Factor Receptor 2 (FGFR2), Limbic System-Associated Membrane Protein (LSAMP), and Neurotrimin (NTM) mRNA levels were significantly higher compared to controls, while ADAM Metallopeptidase Domain 10 (ADAM10), a metalloprotease releasing NEGR1 from neuronal membranes, was significantly reduced. Interestingly, ADAM10 expression negatively correlated with the behavioural z-score, whereas NEGR1 and LSAMP expression showed positive correlations. Conclusions: These findings indicate a potential role for NEGR1 in depressive-like behaviors elicited in a stress-susceptible phenotype. Considering NEGR1 genetic association with depression, our results suggest that the NEGR1 pathway may contribute to depression pathophysiology by modulating the interplay between genetic predisposition and exposure to stress as a crucial environmental precipitating factor.