The development and validation of a maternal immune activation (mIA) animal model relevant to neurodevelopmental disorders: A focus towards Autism Spectrum Disorder (ASD)

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Abstract

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder (NDD) which, despite much research, is not well understood. The heterogeneity of ASD patient cohorts supports the hypothesis of complex interactions of genetic and environmental mechanisms in its aetiology and severity. The presence of gastrointestinal (GI) disturbances in ASD patients that disrupt the bi-directional signalling of the gut-brain axis, suggest that this may play a role in the manifestation of ASD phenotypes. There is also accumulating evidence for the role of neuroinflammatory processes, in both pregnant mother and affected offspring, in the aetiology of NDDs. The increased risk of ASD following infection during pregnancy highlights maternal immune activation (mIA) as a key animal model for NDDs (notably for schizophrenia and ASD) where relevant behavioural phenotypes manifest in the offspring of mIA dams. ASD remains a poorly managed NDD, with no evidence-based therapies for prevention or treatment currently available. Validating new mIA models and refining current methods is vital to the development of new therapeutic strategies. This thesis has explored the development of an mIA model to test the maternal infection hypothesis using exposure to the viral mimetic polyinosinic-polycytidylic acid (poly (I:C)) administered mid-way through pregnancy (gestational day (GD) 12.5) in rats. First, the acute effects of poly (I:C) in non-pregnant female rats were investigated, providing a validation of the experimental methods (strain, route of administration and dose). Separate cohorts of Wistar rats were then used in the GD12.5 mIA model and the physiological responses to 10 mg/kg i.p. poly (I:C) measured. Various measures including elevation of plasma IL-6 and changes in core body temperature were found to be variable between treated dams. These results confirmed the need to standardise analysis of mIA in dams, to correlate maternal inflammation with subsequent offspring outcomes such as phenotype and neuronal development changes. Poly (I:C) batch differences were also thought to contribute to these variable results and refinement of mIA methods are proposed. Longitudinal effects of mIA on offspring of both sexes were investigated including their developmental trajectory measuring specific gene expression, morphology at GD21 and post-natal day (PD) 21, and behavioural phenotyping at adolescence and adulthood. Gestational and early postnatal changes in offspring following mIA have yet to be systematically explored. Gene expression analysis at GD21 and PD21 in offspring shows that this mIA model is useful for the identification of early developmental changes relevant to NDDs. Moreover, analysis of gene expression changes related to synaptic function, glial cells and blood-brain barrier integrity demonstrated that changes were dependent on both sex and brain region of interest. This confirms the need to include both sexes of offspring and inclusion of different brain regions for analysis which is a common limitation of previous preclinical mIA studies. The investigation of protein level changes is required to determine functional relevance, the results obtained provide evidence for subsequent targeted protein analysis in this model. Changes to the development of the gut microbiota were investigated at PD21. mIA produced a non-significant reduction in the diversity of the faecal microbiota, however at a more specific level, significant upregulation of Clostridiales was found. Further validation of microbial changes at the genus level will determine the biological relevance of these findings. This is a critical area for further studies in this model in order to understand the interaction between the gut and brain in ASD, since changes to the gut microbiota are common in ASD patients. A robust analysis was conducted to target key behavioural symptoms of ASD at adolescence and into adulthood in the mIA model with identification of an anxiety-like phenotype in male offspring at adolescence. In conclusion, these studies have demonstrated previously unknown effects of mIA through the investigation of the immune response in pregnant dams following poly (I:C) exposure alongside an in depth, developmental analysis of brain, behaviour and gut in both male and female offspring. The results suggest that 10 mg/kg i.p. poly (I:C) in Wistar rats is a useful model to study the mechanisms of mIA in relation to ASD, including the role of gut dysbiosis in anxiety-like behaviour relevant to specific ASD phenotypes in the clinical setting.

Keyword(s)

animal model; maternal immune activation; neurodevelopmental

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