THE SPATIAL COGNITIVE DYSFUNCTION AND MICROGLIAL ACTIVATION INDUCED BY ADOLESCENT SOCIAL ISOLATION THROUGH THE HYPOPRODUCTION OF CYSTINE BY THE DAMAGE OF COLONIC GOBLET CELLS

Abstract Background Adverse experiences such as bullying and abuse in adolescence increase the risk of developing psychiatric diseases in adulthood. However, it is poorly understood how adverse experiences lead to the pathogenesis of psychiatric diseases. Intestinal homeostasis in the gut-brain axis is susceptible to adolescent stress. Aims & Objectives In the present study, we investigated whether an adolescent social isolation (SI) after weaning induces behavioral abnormalities through disrupted colonic function. Method After mice were exposed to SI (isolation from 3 to 7 weeks of age), the gut microbiota was analyzed by metagenomic analysis in feces. Spatial memory function was evaluated by a novel object location test in SI-exposed mice. Metabolomic analysis in serum was analyzed by liquid chromatography-mass spectrometry (LC-MS). Results Adolescent mice exposed to SI showed spatial memory dysfunction in the novel object location test, and activation of microglia in the hippocampus (HIP). Interestingly, SI decreased the differentiation of goblet cells which produce mucin. The composition of gut microbiota was also altered by SI. Particularly SI depleted Akkermansia muciniphila (A. muciniphila) feeds on mucin. The decrease of goblet cells by SI reduced homocysteine-related metabolites in serum. The administration of rebamipide, which promotes the differentiation of goblet cells in the colon, attenuated SI-induced not only the impairment of spatial memory, the activation of microglia in the HIP, but also the decrease of cystine, a downstream metabolite of homocysteine. Interestingly, the serum cystine levels correlated with spatial memory function. Further, the administration of cystine ameliorated not only SI-induced spatial memory impairment, but also microglial activation and increase of microglial C-C motif chemokine ligand 7 (CCL7) in the hippocampus. Discussion & Conclusion These findings suggest that adolescent SI decreased serum cystine level via damage of colonic goblet cells resulting in the spatial cognitive deficits and microglia activation in the hippocampus.