Behavioural and developmental consequences of maternal immune activation in offspring

Abstract

Schizophrenia is a neurodevelopmental disorder (NDD) with debilitating symptoms, of which those in the cognitive domain (e.g. cognitive flexibility) are poorly treated by currently licensed medications. Exposure to viral, bacterial, or parasitic infections during pregnancy has been shown to increase risk for NDDs in offspring. This suggests that the effects of maternal immune activation (MIA) are due to inflammatory mediators, such as the pro-inflammatory cytokines interleukin (IL)-6 and tumour necrosis factor alpha (TNF-α). The postnatal maternal environment is also a critical period whereby maternal care behaviours promote normal development of the offspring brain. Impaired or attenuated maternal care in humans and rodents increases risk for NDDs in the adolescent and adult offspring. To understand the mechanistic pathways that link acute MIA with chronic NDDs in offspring, animal models are widely used. Such models commonly involve administration of immunogens into pregnant rodents, including the synthetic double-stranded RNA polyinosinic:polycytidylic acid (poly I:C) which mimics viral infection by binding to toll-like receptor 3. Whilst the poly I:C model has been used to investigate the contributions of the prenatal and postnatal maternal environments on offspring cognition in mice, this has not been investigated in rats, which offer significant benefits as a model system for complex cognitive and social behaviours. The experiments in this thesis involved systemic administration of poly I:C on gestational day (GD)-15 in Wistar rats to investigate effects on the early postnatal maternal environment and its contribution to the pathogenesis of cognitive deficits in offspring. The biomolecular characteristics of poly I:C (molecular weight, endotoxin contamination) were first investigated as a potential source of maternal and fetal phenotypic variability. Following this, a specified low molecular weight (LMW) and endotoxin-free poly I:C from InvivoGen was used. The effect of poly I:C on maternal weight (post-treatment and until GD21), the maternal pro-inflammatory response (plasma IL-6 and TNF-α at 3 h post-treatment), and litter composition was recorded. Pups were either left in the home litter or cross-fostered on postnatal day (PD)-1. During the early postnatal period (PD6-14), pup communicative behaviour (ultrasonic vocalisations, USVs) and maternal-offspring interactions were recorded. After weaning, female and male offspring were monitored for weight gain and tested on a battery of cognitive tasks (novel object recognition, NOR; elevated plus maze, EPM; social interaction, SI; radial arm maze, RAM; attentional set-shifting task, ASST) during adolescence (PD35), adulthood (PD100-125), or both. Offspring brain tissue was taken during adolescence and adulthood to investigate the effect of poly I:C on global DNA methylation, gene expression (Rln, Dnmt1, Pvalb, Sst, Gad1, Gad2, Slc6a1), and protein expression (GAD67, PVALB). Poly I:C induced a significant increase in maternal plasma TNF-α at 3 h post-treatment and reduced maternal weight gain from GD15-21. There was a variable effect of poly I:C on maternal weight loss at 6 and 24 h post-treatment and maternal behaviours. The prenatal maternal response to poly I:C programmed an increase in pup USVs and reduced postnatal weight gain. Similarly, prenatal poly I:C exposure programmed a significant and clinically-relevant deficit in cognitive flexibility in the ASST in adult offspring. This was observed in both females and males and was not found to be affected by alterations to the postnatal maternal environment. In the offspring brain, poly I:C induced a sex, postnatal age, and region-specific change in global DNA methylation (e.g. reduction in the PD35 female dorsal hippocampus, DHipp) and gene expression (e.g. reduced Rln in the PD175 DHipp), but had no effect on expression of GAD67 and PVALB protein in the adult offspring prefrontal cortex. Prenatal MIA using poly I:C pr

Date of Award	1 Aug 2021
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Jocelyn Glazier (Supervisor), Reinmar Hager (Supervisor) & Joanna Neill (Supervisor)