Schizophrenia is a neurodevelopmental disorder defined by posiive (e.g. hallucinaions) and negaive symptoms (e.g. social withdrawal) as well as cogniive dysfuncion. Schizophrenia risk is not only increased by the presence of geneic variants, but also environmental factors. These factors include infecion during gestaion (maternal immune acivaion, MIA) or early-life stress. The biological mechanisms through which these insults impart their risk and why some individuals appear resilient to them remains unclear. We modelled two environmental risk factors in rats using gestaional day 15 administraion of the viral mimeic poly(I:C) and/or limited bedding (LBN), respecively. Adolescent and adult offspring were analysed on schizophrenia-relevant behavioural tasks such as novel object recogniion (NOR). To begin establishing the underlying biological mechanisms, I further invesigated the expression of GABAergic (Pvalb, Gad1, Gad2), glutamatergic (Grin1, Grin2a) and stress-response (Nr3c1, Fkbp5) genes using real-ime quanitaive polymerase chain reacion (RT-qPCR). MIA induced maternal bodyweight changes as well as cytokine elevaions (e.g. IL-6 and TNF-Î±) in maternal plasma and the fetal brain. LBN altered dam behaviour and reduced offspring bodyweight. Adolescent MIA and LBN offspring exhibited deficits in NOR; these effects were alenuated by adulthood. Adolescent LBN offspring showed increased anxiety behaviour and altered sociability. LBN and MIA reduced average adult sucrose consumpion, though the magnitude depended on prenatal treatment and sex, respecively. These results suggest that MIA and LBN recapitulate key phenotypes of schizophrenia both separately and together. Further, my results show that sex appears an important mediator in the effects of both pre- and postnatal insults and highlight potenial mechanisms (e.g. prenatal inflammaion) through which they exert their effects. Adolescents exhibited reducions in Grin1 in the dorsal hippocampus (dHPC) and trends towards sex-specific alteraions to prefrontal (PFC) Pvalb and Gad2. An increase in Fkbp5 was seen in the adult MIA PFC, as were trends towards altered Pvalb gene expression in the PFC of offspring. Overall, both MIA and LBN elicit differing molecular phenotypes across development, though GABAergic dysfuncion is conserved. Clustering of behavioural and molecular traits idenified two subgroups of offspring at all imepoints. Approximately half of MIA fetuses exhibited high inflammaion. All adolescent treatment groups except vehicle had approximately equal high- and low- performance. All adult groups exhibited distribuion to both groups. Re-analysis of RT-qPCR data suggests that behavioural variability in MIA offspring may be due to differenial expression of glutamatergic and GABAergic genes, suggesing excitatory/inhibitory imbalance in key neural circuits. The data presented in my thesis offers insight into the mechanisms that drive the effects of MIA and LBN, while highlighing methods that idenify individuals exposed to idenical treatments that exhibit opposing phenotypes. Future research should employ similar straificaion methods to draw stronger links between molecular and behavioural phenotypes in models of environmental risk. This could include single- cell or electrophysiological methodologies which could further characterise excitatory/inhibitory dysfuncion within those that present with the phenotype.
- maternal immune activation
- early life stress