Nod2 deficiency exacerbates schizophrenia-related alterations in offspring of maternal immune activation in a sex-dependent manner

Abstract

Introduction: Schizophrenia is a severe mental disorder with a complex etiopathogenesis involving both genetic and environmental risk factors. Evidence suggests that immune dysregulation plays a key role in its development, with maternal immune activation (MIA) during pregnancy identified as a significant environmental contributor. However, not all maternal infections result in schizophrenia-like outcomes, indicating that genetic susceptibility may render some individuals more vulnerable to MIA. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), an intracellular receptor, plays a crucial role in maintaining the balance between intestinal microbiota and immune responses, but its precise role in gut-brain interactions during neurodevelopment remain unclear.

Methods: To investigate the interaction between MIA and Nod2 deficiency, we evaluated behavioral and physiological phenotypes in Nod2^-/- mice exposed to poly(I:C)-induced MIA. In addition to immune responses, we analyzed maternal gut microbiota and the transmission of microbiota between mothers and offspring. Given the role of the gut-brain axis in schizophrenia, we conducted intestinal immunofluorescence staining, organoid cultures, and RNA sequencing of fetal brains to assess gut injury and neuroimmune changes in the brain. Male and female offspring were analyzed separately.

Results: Dual exposure led to schizophrenia-like behaviors in a sex-specific manner, as well as brain development disruptions, compromised gut integrity, reduced intestinal organoid-forming capacity, and altered gut microbiota composition. Importantly, maternal gut microbiota disturbances, coupled with microbial transmission to offspring, appear to increase schizophrenia risk with potential long-term behavioral consequences.

Conclusion: This study underscores the intricate interplay of genetic, environmental, and microbiome factors, offering a valuable model for investigating the complex pathophysiology of neurodevelopmental disorders.

Keywords: Double-hit model; Gut microbiota; Maternal immune activation; Mother-to-offspring microbial transmission; NOD2 knockout; Schizophrenia.