Brain gene expression in a novel mouse model of postpartum mood disorder

Abstract

Introduction: Steroid sulfatase (STS) is an enzyme which cleaves sulfate groups from a variety of steroid hormones, thereby altering their activity and solubility. The expression and activity of STS is increased in female mammalian tissues (including brain) during late pregnancy and into the postpartum period. STS-deficient human and mouse mothers (as a consequence of genetic mutation or acute pharmacological manipulation) show evidence for elevated psychopathology and abnormal behaviour respectively in the postpartum period. In mice, these behavioural effects can be partially normalised through administration of the antipsychotic ziprasidone. Methods:To explore the neurobiology underlying these postpartum behavioural effects, we compared whole brain gene expression by microarray in behaviourally-defined new mouse mothers acutely administered the STS inhibitor 667-Coumate (10mg/kg p.o.) or vehicle solution (n=12 per group); significant changes were followed-up with pathway analysis and quantitative polymerase chain reaction (qPCR). Finally, the effects of combined 667-Coumate and antipsychotic (ziprasidone) administration (0, 0.3 and 1.0mg/kg i.p.) on the brain expression of the most robustly differentially-expressed candidate genes was examined (n≥7 per group). Results: Surprisingly, no significant gene expression changes were detected between vehicle and 667-Coumate-treated brains at a False Discovery Rate (FDR) corrected p<0.1. 1,081 unique expression changes were detected at a less-stringent cut-off of p<0.05, just two top hits were verified by qPCR, and pathway analysis indicated a significant enrichment of genes involved in olfactory transduction (corrected p-value=1.8x10 -3 ). The expression of the two most robust differentially-expressed genes (Stoml3 and Cyp2g1) was not affected by ziprasidone administration. Conclusions:Behavioural abnormalities in new mothers in the postpartum period elicited as a result of STS deficiency are likely to be the culmination of many small gene expression changes. Our data are consistent with the idea that olfactory function is key to postpartum maternal behaviour in mice, and suggest that aberrant expression of olfactory system genes may partially underlie abnormal maternal behaviour in STS-deficient women.

Brain gene expression in a novel mouse model of postpartum mood disorder

“…The work was performed within the Medical Research Council Centre for Neuropsychiatric Genetics and Genomics (Centre grant MR/ L010305/1) and was funded by a Neuroscience and Mental Health Research Institute, Cardiff University seedcorn grant to TH and WD. This manuscript has been released as a preprint at bioRxiv [41]. The study sponsors had no role in study design, collection, analysis or interpretation of data, writing of the paper, or the decision to submit for publication.…”