Abstract
Under 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 underscored JAG1 as the most promising candidate. Combined with further validation with real-time PCR, downregulation of NOTCH1 was statistically significant. Accordingly, we reverse-translated the significant finding from a surrogate tissue for neurons, and studied the behavioral profile of Notch1+/− 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 of NOTCH1 or JAG1. In our first episode psychosis cohort, we observed a specific correlation between the expression of JAG1 and a face processing measure only in male patients. The expression of JAG1 was 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.
Highlights
Through the advancement of psychiatric genetics, many biological pathways have been underscored in association with neuropsychiatric disorders [1–6]
Some genes that were originally highlighted in studies with specific pedigrees may not be well reproduced as major risk factors in genome wide association studies (GWASs), which include genes for Notch signaling, in particular NOTCH4, for schizophrenia (SZ) [7–13]
As a complementary approach to look for the molecular drivers of the pathophysiology of neuropsychiatric disorders, molecular expression studies using tissue from patients and healthy subjects are well appreciated [14–18]
Summary
Through the advancement of psychiatric genetics, many biological pathways have been underscored in association with neuropsychiatric disorders [1–6]. As a complementary approach to look for the molecular drivers of the pathophysiology of neuropsychiatric disorders, molecular expression studies using tissue from patients and healthy subjects are well appreciated [14–18]. Olfactory neural epithelium is accessible in living people via nasal biopsy, and multiple research groups have utilized this surrogate tissue to obtain molecular signatures relevant to the brain [16, 21–23]. We hypothesized that olfactory neural epithelium gene expression profiles might be useful to look for diseaserelevant neuronal signatures, in particular obtaining possible molecular leads to initiate a biological study for neuropsychiatric disorders. We examined microarray gene expression in the neural tissue and underscored Notch–JAG pathway molecules in association with SZ.
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