Global metabolic profiles in a non-human primate model of maternal immune activation: implications for neurodevelopmental disorders

• Published in: Molecular psychiatry 2022-12, Vol.27 (12), p.4959-4973
• Main Authors: Boktor, Joseph C., Adame, Mark D., Rose, Destanie R., Schumann, Cynthia M., Murray, Karl D., Bauman, Melissa D., Careaga, Milo, Mazmanian, Sarkis K., Ashwood, Paul, Needham, Brittany D.
• Format: Article
• Language: English
• Subjects: 101/58; 631/378; 631/45; Amino acids; Animal models; Animals; Behavior, Animal - physiology; Behavioral Sciences; Biological Psychology; Cerebrospinal fluid; Cytokines; Disease Models, Animal; Epidemiology; Female; Humans; Immune response; Intestine; Male; Medicine; Medicine & Public Health; Mental disorders; Metabolism; Metabolites; Metabolome; Metabolomics; Neurodevelopment; Neurodevelopmental Disorders; Neurosciences; Offspring; Pharmacotherapy; Phenotypes; Pregnancy; Prenatal Exposure Delayed Effects; Primates; Psychiatry; Risk factors; Schizophrenia
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/s41380-022-01752-y

Epidemiological evidence implicates severe maternal infections as risk factors for neurodevelopmental disorders, such as ASD and schizophrenia. Accordingly, animal models mimicking infection during pregnancy, including the maternal immune activation (MIA) model, result in offspring with neurobiological, behavioral, and metabolic phenotypes relevant to human neurodevelopmental disorders. Most of these studies have been performed in rodents. We sought to better understand the molecular signatures characterizing the MIA model in an organism more closely related to humans, rhesus monkeys ( Macaca mulatta ), by evaluating changes in global metabolic profiles in MIA-exposed offspring. Herein, we present the global metabolome in six peripheral tissues (plasma, cerebrospinal fluid, three regions of intestinal mucosa scrapings, and feces) from 13 MIA and 10 control offspring that were confirmed to display atypical neurodevelopment, elevated immune profiles, and neuropathology. Differences in lipid, amino acid, and nucleotide metabolism discriminated these MIA and control samples, with correlations of specific metabolites to behavior scores as well as to cytokine levels in plasma, intestinal, and brain tissues. We also observed modest changes in fecal and intestinal microbial profiles, and identify differential metabolomic profiles within males and females. These findings support a connection between maternal immune activation and the metabolism, microbiota, and behavioral traits of offspring, and may further the translational applications of the MIA model and the advancement of biomarkers for neurodevelopmental disorders such as ASD or schizophrenia.