Sex differences and sex-dependent effects of maternal immune activation and raloxifene on neurotransmitter gene expression in the adult rat dorsal striatum.

Abstract

Maternal immune activation (MIA) is a risk factor for neurodevelopmental disorders such as schizophrenia, where sex differences in incidence, symptom profile, and treatment response are observed. Dysfunction across dopaminergic, gamma-aminobutyric acid (GABA)-ergic, and glutamatergic circuits involving the dorsal striatum (dSTR) contribute to schizophrenia symptoms. The selective estrogen receptor modulator (SERM), raloxifene, has therapeutic benefit that appears to be sex dependent. The differential male-female effects of raloxifene on dSTR neurotransmission impacted by MIA are not fully understood. We investigated sex differences and the sex-dependent impact of late-gestation MIA and chronic raloxifene treatment on neurotransmitter-related molecules in the adult rat dSTR. Using a high molecular weight poly(I:C) MIA model (gestational day 19) and chronic raloxifene treatment (5 mg/kg/day, oral) of offspring on postnatal days 58-84, we quantified mRNA expression of dopaminergic-, GABAergic-, and glutamatergic-related, and protein expression of dopaminergic-related signalling molecules in the dSTR of adult male and female offspring. We identified significant sex differences in dSTR molecular profiles relating to dopaminergic activity, astrocyte activity and inhibitory interneuron markers, and sex-dependent molecular consequences of MIA and raloxifene treatment on dopaminergic-related gene and protein expression and of MIA on astrocytic GABA synthesis enzyme transcripts. This study highlights the importance of sex as a biological variable and identifies candidate molecular pathways through which prenatal immune insult and estrogen receptor modulation may influence vulnerability and treatment response in neurodevelopmental disorders.