Advancing Autism Research From Mice to Marmosets: Behavioral Development of Offspring Following Prenatal Maternal Immune Activation

Abstract

Understanding the mechanism(s) by which maternal immune activation (MIA) during gestation may disrupt neurodevelopment and increase the susceptibility for disorders such as autism spectrum disorder (ASD) or schizophrenia is a critical step in the development of better treatments and preventive measures. A large body of literature has investigated the pathophysiology of MIA in rodents. However, a translatability gap plagues pre-clinical research of complex behavioral/developmental diseases and those diseases requiring clinical diagnosis, such as ASD. While ideal for their genetic flexibility, vast reagent toolkit, and practicality, rodent models often lack important elements of ethological validity. Hence, our study aimed to develop and characterize the prenatal MIA model in marmosets. Here, we adapted the well-characterized murine maternal immune activation model. Pregnant dams were administered 5 mg/kg poly-L-lysine stabilized polyinosinic-polycytidylic acid (Poly ICLC) subcutaneously three times during gestation (gestational day 63, 65, and 67). Dams were allowed to deliver naturally with no further experimental treatments. After parturition, offspring were screened for general health and vigor, and individual assessment of communication development and social behavior was measured during neonatal or adolescent periods. Similar to rodent models, offspring subjected to MIA exhibited a disruption in patterns of communication during early development. Assessment of social behavior in a marmoset-modified 3-chamber test at 3 and 9 months of age revealed alterations in social behavior that, in some instances, was sex-dependent. Together, our data indicate that marmosets are an excellent non-human primate model for investigating the neurodevelopmental and behavioral consequences of exposure to prenatal challenges, like MIA. Additional studies are necessary to more completely characterize the effect of prenatal inflammation on marmoset development and explore therapeutic intervention strategies that may be applicable in a clinical setting.

COVID-19 in pregnancy: implications for fetal brain development

“…MIA is a primary link between maternal viral infection and offspring neurodevelopmental disorders Convergent data from animal models have demonstrated that MIA, rather than a specific virus or bacterial infection, is likely the final common pathway by which most maternal infections confer offspring neurodevelopmental morbidity [42,43]. Rodent and non-human primate models have utilized multiple techniques to activate the maternal immune system, including the viral mimic polyinosinic:polycytidylic (poly[I:C]), a synthetic double-stranded RNA, demonstrating alterations in offspring brain immune function, and behavioral and neuroimaging correlates of ASD and schizophrenia [42,[44][45][46][47][48][49][50][51][52][53].…”

Primate Models as a Translational Tool for Understanding Prenatal Origins of Neurodevelopmental Disorders Associated With Maternal Infection

“…4.4 Marmoset maternal Poly IC models. The recently established marmoset MIA model ( 148 ) provides an opportunity to explore the impact of prenatal immune challenge in a species that is playing an increasing role in neurodevelopmental research. For a NHP, marmosets are comparatively small, have a higher reproductive efficiency with respect to gestation, delivery intervals, and litter size, and overall have a shorter life history and development, becoming sexually mature at around 1.5 years old ( 149 ).…”

Assessment of the effects of sex, age, and rearing condition on ultrasonic vocalizations elicited by pups during the maternal potentiation paradigm in C57BL/6J mice

“…This suggests that repertoire alteration might be more sensitive to this paradigm than the total number of calls. Although the meaning of the repertoire changes we found in our study is unknown, alteration in the vocal repertoire is a common finding in animal models of developmental disorders in rodents (Binder & Lugo, 2017;Nolan et al, 2020;Romano et al, 2013; and primates (Santana-Coelho et al, 2021), suggesting that these findings can have significant translatability.…”