Investigating the Effect of Reduced Serotonin Transporter Expression in a Maternal Immune Activation Model of Neurodevelopmental Disorders

Abstract

<p>Maternal Immune Activation (MIA) during early pregnancy is an established risk factor for the occurrence of neurodevelopmental disorders such as Autism Spectrum Disorder (ASD) and schizophrenia (SCZ) in offspring. Serotonin signalling is also implicated in both ASD and SCZ, in conjunction with a known and extensive influence in neural development. Using a Wistar serotonin transporter (SERT) knockout model to mimic allelic variation in the human serotonin transporter promoter (5‐HTTLPR), this research investigates the impact of full or reduced SERT function on the effect of poly I:C-induced MIA in offspring. Experimental design focuses on ultrasonic vocalisation communication in postnatal day (PND) 7 offspring, followed by genetic expression of the Rac1/Kal7/Disc1 signalosome pathway at PND21 previously implicated in SCZ pathology. Results from behavioural analysis of pups indicate a statistically significant increase in calling and call complexity in pups heterozygous for the SERT (SERT HET) compared to wildtype (WT). When separated by sex, this trend remains consistent however only reaches significance in male offspring. Male SERT HET pups also a significant treatment effect in call complexity, and a significant genotype/treatment interaction which suggests an increased susceptibility to MIA-induced behavioural effects. Additionally, poly I:C exposed pups show increased expression of Disc1, supporting evidence that this pathway may be affected in neurodevelopmental disorders. No genotype and sex effects were observed in signalosome expression; however, this study may be too underpowered to detect these effects. These results suggest that differences between sex and SERT genotype in offspring may modulate the behavioural effects of MIA in rodent models of NDD, with more study required to assess these differences in a molecular context. Furthermore, this study aims to address the overall inconsistency and misrepresentation of statistical methods in MIA models by employing MIA validation tests and linear mixed modelling to account for litter variation. In summary, the research presented in this thesis reports initial evidence suggesting SERT genotype may influence the effect of MIA, however further research is necessary to characterise the effect of genotype on MIA challenge during gestation.</p>