Hyperandrogenization and late gestational infection result in an autism-like phenotype in a rodent model

Burke, Francine F. (2023) Hyperandrogenization and late gestational infection result in an autism-like phenotype in a rodent model. Masters thesis, Memorial University of Newfoundland.

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Abstract

Autism spectrum disorder (ASD) is characterized by persistent difficulties with communication, social behaviour, and repetitive behaviour, and disproportionately affects males compared to females. Maternal immune activation (MIA) resulting from gestational infections can disrupt fetal neurodevelopment, increasing the risk for neurodevelopmental disorders such as ASD. Rodent models of MIA produce offspring with an ASD-like phenotype and demonstrate a sex bias mirroring the human condition. Sex differences in brain and behaviour are largely attributable to the prenatal androgen surge during late gestation which acts to masculinize the male brain. In the current study, I assessed whether prenatal androgens mediate the sex bias in MIA-associated deficits. I manipulated MIA both prior to (embryonic day [E] 12.5) and during (E17.5) the prenatal androgen surge (i.e., early and late gestation, respectively), and in the presence or absence of exogenous androgen treatment. Offspring of both sexes were assessed for communicative, social, and repetitive behaviour deficits. The findings support male vulnerability to MIA deficits, that is dependent on the timing of gestational infection, such that the greatest deficits were found when MIA coincided with the prenatal androgen surge. Exogenous androgens did not have an additive effect of exacerbating deficits in late gestational MIA; instead, hyperandrogenization in the absence of MIA resulted in behavioural deficits comparable to those of MIA offspring. These results suggest that high androgen signalling alone is capable of producing an ASD-like phenotype, supporting the use of hyperandrogenization as a rodent model of ASD. Overall, these findings indicate that the maternal immune system can influence offspring brain and behaviour in a sex- and time-dependent manner, and suggest that prenatal androgens contribute to the greater risk of ASD in males than females.

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