Prenatal exposure to high- but not low-molecular-weight poly(I:C) produces selective sociability deficits in
Daniela Kuncicka1, Simona Ondráčková2, Karin Estokova2
1Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic; Second Faculty of Medicine, Charles University, Prague, Czech Republic.
Insights
High-molecular-weight poly(I:C) exposure during pregnancy robustly impairs social behavior in offspring, unlike low-molecular-weight poly(I:C). This highlights molecular weight as crucial for modeling autism spectrum disorder (ASD) through maternal immune activation (MIA).
Area of Science:
- Neuroscience
- Developmental Biology
- Immunology
Background:
- Maternal immune activation (MIA) models are used to study prenatal inflammation's impact on autism spectrum disorder (ASD).
- The immune response to polyinosinic:polycytidylic acid (poly(I:C)) varies with its molecular weight.
- Poly(I:C) molecular composition may influence the development of social deficits in offspring.
Purpose of the Study:
- To investigate if the molecular weight of poly(I:C) affects social behavior deficits in offspring following MIA.
- To determine if high-molecular-weight (HMW) or low-molecular-weight (LMW) poly(I:C) is a more valid model for ASD-associated prenatal immune challenges.
Main Methods:
- Pregnant Wistar rats were injected with HMW or LMW poly(I:C) on gestational day 14.
- Offspring were assessed for social behavior (homing response, social interaction) and general activity (open field, elevated plus maze).
- Data were analyzed using nested linear mixed models.
Main Results:
- HMW poly(I:C) significantly impaired neonatal homing responses and adult social investigation in both sexes.
- HMW-exposed males showed increased social approach, while both HMW- and LMW-exposed males exhibited hyperlocomotion.
- Only HMW poly(I:C) exposure led to robust deficits in early social communication and adult social behavior.
Conclusions:
- The molecular weight of poly(I:C) is a critical determinant of MIA model outcomes.
- HMW poly(I:C) is a more reliable and translationally valid preparation for modeling ASD-associated prenatal immune challenges.
- Prenatal exposure to HMW poly(I:C) induces significant and lasting social deficits in offspring.
Abstract:
Social deficits following maternal immune activation (MIA) are widely used to model the impact of prenatal inflammation on autism spectrum disorder (ASD). Since the immune response to polyinosinic:polycytidylic acid (poly(I:C)) depends on its molecular weight, we hypothesized that poly(I:C) molecular composition shapes the emergence of social deficits in offspring. Pregnant Wistar rats received a single subcutaneous injection of low- or high-molecular-weight poly(I:C) (LMW or HMW; 10 mg/kg) on gestational day 14. Offspring of both sexes were assessed for social behavior in early life and adulthood using the homing response and social interaction tests, respectively. Open field and elevated plus maze tasks controlled for locomotor activity and anxiety-like behavior. Data were analyzed using nested linear mixed models accounting for litter and cohort effects. HMW, but not LMW, poly(I:C) significantly impaired neonatal homing responses, indicating early disruption of maternal affiliation. In adulthood, HMW-exposed offspring of both sexes showed reduced social investigation, with males additionally exhibiting increased social approach. Furthermore, both HMW- and LMW-exposed males displayed hyperlocomotion and increased time in the centre of the open field, without accompanying changes in anxiety-like behavior. In summary, although both HMW- and LMW-exposed offspring showed alterations in basal activity, only HMW poly(I:C) produced robust deficits in early social communication and adult social behavior. These findings identify molecular weight as a key determinant of MIA model outcomes and support HMW poly(I:C) as the more reliable and translationally valid preparation for modeling ASD-associated prenatal immune challenges.
