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

Published:September 09, 2013DOI:https://doi.org/10.1016/j.biopsych.2013.06.025

      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.

      Key Words

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      Linked Article

      • Is There a Flame in the Brain in Psychosis?
        Biological PsychiatryVol. 75Issue 4
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          For many decades, it was believed that the brain was immunologically privileged, hence it was surprising when Shatz and colleagues (1) reported in 2000 that a number of immune proteins (cytokines and major histocompatibility complex [MHC] proteins) were not just present in the brain but were localized at functional synapses. Subsequent work has shown that these molecules play a major role in brain development as well as in mature synaptic function and plasticity (2,3).
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