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Molecular Psychiatry (2022 )Cite this article
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.
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Scripts for data-visualization and statistical analysis of correlations, pathway enrichment, and microbiome analysis are available at: https://github.com/jboktor/NHP_MIA_Omics.
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We thank the veterinary and animal services staff of the CNPRC for care of the animals. Poly ICLC was kindly provided by Dr. Andres Salazar, MD, Oncovir, Washington D.C.
This work was supported by grants from Autism Speaks (Grant #7567 to PA, and SKM); the Johnson Foundation (to PA); the Brain Foundation (to PA and to SKM); NARSAD Foundation (to PA); Axial Biotherapeutics (to SKM); and the National Institutes of Health (HD090214 to PA) and (MH100556 to SKM). Development of the animal model was supported by a grant from the Simons Foundation to the late Dr. Paul Patterson (SFARI 9900060), with additional support provided by the base grant (RR00169) of the California National Primate Research Center (CNPRC), a gift from Ted and Ginger Jenkins and a UC Davis RISE Award (to PA and MB).
Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA
Joseph C. Boktor, Mark D. Adame & Sarkis K. Mazmanian
Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, 95616, USA
Destanie R. Rose, Milo Careaga & Paul Ashwood
The M.I.N.D. Institute, University of California, Davis, Sacramento, CA, 95817, USA
Destanie R. Rose, Cynthia M. Schumann, Karl D. Murray, Melissa D. Bauman, Milo Careaga & Paul Ashwood
Department of Anatomy, Cell Biology & Physiology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
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MDB, CMS, KDM, and MC worked directly with the NHPs and collected samples. DRR performed immune profiling. JCB, MDA, and BDN analyzed metabolomics data and wrote the manuscript. SKM, PA and MDB secured funding for the project. All authors edited the manuscript.
Correspondence to Paul Ashwood or Brittany D. Needham.
SKM has financial interest in Axial Biotherapeutics. JCB, MDA, DRR, CMS, KDM, MDB, MC, PA, and BDN report no financial conflicts of interest.
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Boktor, J.C., Adame, M.D., Rose, D.R. et al. Global metabolic profiles in a non-human primate model of maternal immune activation: implications for neurodevelopmental disorders. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01752-y
DOI: https://doi.org/10.1038/s41380-022-01752-y
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