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.
Highlights
The etiology of neurodevelopmental disorders (ND) such as autism spectrum disorder (ASD) and schizophrenia remains poorly defined
A dose-dependent immune response to Poly ICLC treatment was confirmed in non-breeding adult female marmosets in a pilot experiment performed prior to maternal immune activation (MIA) of pregnant dams. 3.2 mg/kg was identified as the minimum effective dose to cause an increase in the levels of the inflammatory cytokines/chemokines TNF-a (261.5% ± 70 of baseline, p = 0.0278), MIP-1b (154.3% ± 69 of baseline, p = 0.0286), IFN-α (2,450% ± 2,250 of baseline, p = 0.0286), monocyte chemoattractant protein 1 (MCP-1) (228.1% ± 51 of baseline, p = 0.0321) from baseline
Analysis of parental age and weight showed that there were no significant differences between the control, saline control, and poly ICLC groups
Summary
The etiology of neurodevelopmental disorders (ND) such as autism spectrum disorder (ASD) and schizophrenia remains poorly defined. Genetics play an important role in these disorders. Both heritable and de novo gene variations have been identified as causative factors in abnormal neurodevelopment [1, 2]. Studies in monozygotic twins reveal a concordance rate between 60 and 91% for ASD [3], and 41 to 65% for schizophrenia [4]. While dizygotic twins present a low concordance rate [5] demonstrating the considerable role of genetic in these disorders. Myriad environmental factors have been identified to play a putative role in the disruption of neurodevelopment. Prenatal exposure to drugs [6], stress [7, 8], environmental pollutants [9], and infection [10, 11] are linked to increased risk of ASD or schizophrenia
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
