title: Activation of the maternal immune system during pregnancy alters behavioral development of rhesus monkey offspring.
abstract: BACKGROUND
  Maternal infection during pregnancy is associated with an increased risk of schizophrenia and autism in the offspring. Supporting this correlation, experimentally activating the maternal immune system during pregnancy in rodents produces offspring with abnormal brain and behavioral development. We have developed a nonhuman primate model to bridge the gap between clinical populations and rodent models of maternal immune activation (MIA).
  
  
  METHODS
  A modified form of the viral mimic, synthetic double-stranded RNA (polyinosinic:polycytidylic acid stabilized with poly-L-lysine) was delivered to two separate groups of pregnant rhesus monkeys to induce MIA: 1) late first trimester MIA (n = 6), and 2) late second trimester MIA (n = 7). Control animals (n = 11) received saline injections at the same first or second trimester time points or were untreated. Sickness behavior, temperature, and cytokine profiles of the pregnant monkeys confirmed a strong inflammatory response to MIA.
  
  
  RESULTS
  Behavioral development of the offspring was studied for 24 months. Following weaning at 6 months of age, MIA offspring exhibited abnormal responses to separation from their mothers. As the animals matured, MIA offspring displayed increased repetitive behaviors and decreased affiliative vocalizations. When evaluated with unfamiliar conspecifics, first trimester MIA offspring deviated from species-typical macaque social behavior by inappropriately approaching and remaining in immediate proximity of an unfamiliar animal.
  
  
  CONCLUSIONS
  In this rhesus monkey model, MIA yields offspring with abnormal repetitive behaviors, communication, and social interactions. These results extended the findings in rodent MIA models to more human-like behaviors resembling those in both autism and schizophrenia.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis; California National Primate Research Center, University of California, Davis, Davis; The M.I.N.D. Institute, University of California, Davis, Sacramento. Electronic address: mdbauman@ucdavis.edu.
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Bauman
authors.affiliation: Department of Public Health Sciences, Division of Biostatistics, University of California, Davis, Davis.
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Iosif
authors.affiliation: Division of Biology, California Institute of Technology, Pasadena.
authors.forename: Stephen E P
authors.initials: SE
authors.lastname: Smith
authors.affiliation: Division of Biology, California Institute of Technology, Pasadena.
authors.forename: Catherine
authors.initials: C
authors.lastname: Bregere
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis; California National Primate Research Center, University of California, Davis, Davis; The M.I.N.D. Institute, University of California, Davis, Sacramento; Center for Neuroscience, University of California, Davis, Davis, California.
authors.forename: David G
authors.initials: DG
authors.lastname: Amaral
authors.affiliation: Division of Biology, California Institute of Technology, Pasadena.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Patterson
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000196:embryology* / Q000276:immunology* / Q000503:physiopathology; D002266:Carboxymethylcellulose Sodium / Q000031:analogs & derivatives; D004195:Disease Models, Animal; D005260:Female; D008253:Macaca mulatta; D008426:Maternal Deprivation; D018811:Maternal Exposure; D001523:Mental Disorders / Q000209:etiology* / Q000503:physiopathology*; D011070:Poly I-C; D011107:Polylysine / Q000031:analogs & derivatives; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011297:Prenatal Exposure Delayed Effects; D012919:Social Behavior; D013239:Stereotyped Behavior / Q000502:physiology; D014828:Vocalization, Animal / Q000502:physiology
chemical_list: D011107:Polylysine; C019531:poly ICLC; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C
keywords: Animal model; autism spectrum disorder; immune activation; macaque; nonhuman primate; poly IC; schizophrenia