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Activation of the Maternal Immune System During Pregnancy Alters Behavioral Development of Rhesus Monkey Offspring

Bauman, Melissa D. and Iosif, Ana-Maria and Smith, Stephen E. P. and Bregere, Catherine and Amaral, David G. and Patterson, Paul H. (2014) Activation of the Maternal Immune System During Pregnancy Alters Behavioral Development of Rhesus Monkey Offspring. Biological Psychiatry, 75 (4). pp. 332-341. ISSN 0006-3223. doi:10.1016/j.biopsych.2013.06.025.

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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.

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Additional Information:© 2014 Society of Biological Psychiatry. Received Apr 10, 2013; revised Jun 22, 2013; accepted Jun 29, 2013. This work was supported by a grant from the Simons Foundation (SFARI [9900060] to PHP). Additional support was provided by the base Grant (RR00169) of the California National Primate Research Center. Biobehavioral assessments at 3 months of age were carried out by Dr. John Capitanio and funded in part by the National Center for Research Resources (R24RR019970 to JPC and P51RR000169 to California National Primate Research Center) and are currently supported by the Office of Research Infrastructure Programs/Office of the Director (R24OD010962 and P51OD011157, respectively). SEPS is currently affiliated with the Department of Immunology, Mayo Clinic, Rochester, Minnesota. CB is currently affiliated with the Department of Neurosurgery, University Hospital Basel, Basel, Switzerland. We acknowledge the Research Services and Primate Medicine staff at the California National Primate Research Center for care of the animals and to J. Buser, G. Moadab, and A. Lopez for behavioral data collection and assistance with manuscript preparation. Polyinosinic:polycytidylic acid stabilized with poly-L-lysine was kindly provided by Dr. Andres Salazar, M.D., Oncovir, Washington. DC. The authors report no biomedical financial interests or potential conflicts of interest.
Funding AgencyGrant Number
Simons FoundationSFARI 9900060
California National Primate Research CenterRR00169
Subject Keywords:Animal model; autism spectrum disorder; immune activation; macaque; nonhuman primate; poly IC; schizophrenia
Issue or Number:4
Record Number:CaltechAUTHORS:20140210-075449699
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Official Citation:Melissa D. Bauman, Ana-Maria Iosif, Stephen E.P. Smith, Catherine Bregere, David G. Amaral, Paul H. Patterson, Activation of the Maternal Immune System During Pregnancy Alters Behavioral Development of Rhesus Monkey Offspring, Biological Psychiatry, Volume 75, Issue 4, 15 February 2014, Pages 332-341, ISSN 0006-3223, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:43730
Deposited By: Tony Diaz
Deposited On:12 Feb 2014 19:43
Last Modified:10 Nov 2021 16:42

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