Sex-specific involvement of the Notch–JAG pathway in social recognition

Abstract

AbstractUnder the hypothesis that olfactory neural epithelium gene expression profiles may be useful to look for disease-relevant neuronal signatures, we examined microarray gene expression in olfactory neuronal cells and underscored Notch–JAG pathway molecules in association with schizophrenia (SZ). The microarray profiling study underscoredJAG1as the most promising candidate. Combined with further validation with real-time PCR, downregulation ofNOTCH1was statistically significant. Accordingly, we reverse-translated the significant finding from a surrogate tissue for neurons, and studied the behavioral profile ofNotch1+/−mice. We found a specific impairment in social novelty recognition, whereas other behaviors, such as sociability, novel object recognition and olfaction of social odors, were normal. This social novelty recognition deficit was male-specific and was rescued by rapamycin treatment. Based on the results from the animal model, we next tested whether patients with psychosis might have male-specific alterations in social cognition in association with the expression ofNOTCH1orJAG1. In our first episode psychosis cohort, we observed a specific correlation between the expression ofJAG1and a face processing measure only in male patients. The expression ofJAG1was not correlated with any other cognitive and symptomatic scales in all subjects. Together, although we acknowledge the pioneering and exploratory nature, the present work that combines both human and animal studies in a reciprocal manner suggests a novel role for the Notch–JAG pathway in a behavioral dimension(s) related to social cognition in psychotic disorders in a male-specific manner.