Role of pentosidine accumulation in stress-induced social behavioral deficits

The mechanisms underlying schizophrenia, a psychiatric disorder characterized by significant social and behavioral impairments, remain poorly understood. However, glycation stress, driven by the accumulation of advanced glycation end products (AGEs) such as pentosidine, has been implicated in its pathogenesis. Therefore, this study aimed to explore the role of pentosidine in stress-induced social behavioral deficits using a mouse model of social defeat stress (SDS). Mice exposed to SDS displayed individual differences in sociability, and were categorized into stress-susceptible and stress-resilient phenotypes based on their social interaction ratio. Pentosidine levels were significantly elevated in the plasma and the prefrontal cortex (Pfc) of the susceptible group, which correlated with increased social avoidance and decreased interaction times. Administration of pyridoxamine, an AGE synthesis inhibitor, during SDS exposure mitigated these behavioral deficits, and suppressed pentosidine accumulation in both the plasma and Pfc. These findings provide the first evidence linking pentosidine accumulation to stress susceptibility, indicating the involvement of a molecular pathway through which glycation stress influences social behavior. Future studies should further elucidate the mechanisms underlying the effects of pentosidine on behavior, and explore its broader implications in psychiatric disorders.