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. 2014 Feb 15;75(4):332-41.
doi: 10.1016/j.biopsych.2013.06.025. Epub 2013 Sep 5.

Activation of the maternal immune system during pregnancy alters behavioral development of rhesus monkey offspring

Melissa D Bauman  1 , Ana-Maria Iosif  2 , Stephen E P Smith  3 , Catherine Bregere  3 , David G Amaral  4 , Paul H Patterson  3
Affiliations

Activation of the maternal immune system during pregnancy alters behavioral development of rhesus monkey offspring

Melissa D Bauman et al. Biol Psychiatry. .

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.

Keywords: Animal model; autism spectrum disorder; immune activation; macaque; nonhuman primate; poly IC; schizophrenia.

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Conflict of interest statement

The authors report no biomedical financial interests or potential conflicts of interest.

Figures

Figure 1.
Figure 1.
Maternal immune activation (MIA) offspring exhibit abnormal responses to weaning. Although all animals demonstrate a species-typical attachment to their own mother, MIA offspring exhibit an unusual response in the attachment test. Second trimester MIA (MIA2) offspring produce significantly more distress or self-soothing behaviors (i.e., tantrums, convulsive jerk, self-clasp, infant crook tail) than control (CON) offspring. This group difference emerges over the 4 days of testing, with both MIA groups showing a different pattern over time than control animals (p < .001 and p < .003 for the differences in slopes, respectively). Thus, on the final day, MIA2 offspring are highly reactive, control animals are moderately reactive, and first trimester MIA (MIA1) offspring display little evidence of reactivity (p < .01 for difference from control animals for both MIA1 and MIA2 groups on day 4).
Figure 2.
Figure 2.
(A) Maternal immune activation (MIA) offspring exhibit increased frequency of motor stereotypies and self-directed behaviors. Left panel: When observed alone in a large cage at 10 months of age, second trimester MIA (MIA2) animals produce significantly more repetitive behaviors than control animals (CON) (**p ≤ .01). The first trimester MIA (MIA1) offspring also produce more repetitive behaviors than control animals, but this difference does not reach statistical significance at 10 months (p = .06). Middle panel: When observed alone at 22 months of age, MIA1 offspring produce significantly more repetitive behaviors (*p ≤ .05). Second trimester MIA animals also produce significantly more repetitive behaviors than control animals at 22 months (**p ≤ .01). Right panel: When tested at 17 months of age in the Y-maze social preference assay, MIA2 treatment animals produce significantly more repetitive behaviors than control animals (**p ≤ .01). (B) Maternal immune activation offspring display decreased affiliative vocalizations. Left panel: At 22 months, MIA2 offspring produce significantly fewer coo calls than control animals (**p < .01). Right panel: When observed with a novel conspecific at 24 months of age, MIA1 offspring produce significantly fewer coo calls than control animals (*p ≤ .05). (C) Maternal immune activation offspring exhibit inappropriate interactions with unfamiliar conspecifics. Left panel: First trimester MIA offspring demonstrate inappropriate social interactions with an unfamiliar animal, as indexed by high frequency of approaching (*p <0.05) and more frequently moving within arm’s reach of the unfamiliar animal (**p < .01). Right panel: First trimester MIA offspring remained near the unfamiliar animal, as indexed by the duration of time spent in physical contact or within arm’s reach of the unfamiliar animal (*p < .05)
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