The Role of 11β-Hydroxy Steroid Dehydrogenase Type 2 in Glucocorticoid Programming of Affective and Cognitive Behaviours

Fraser J G Shearer, Caitlin S Wyrwoll, Megan C Holmes

Research output: Contribution to journalReview articlepeer-review

9 Citations (Scopus)


Developmental exposure to stress hormones, glucocorticoids, is central to the process of prenatal programming of later life health. Glucocorticoid overexposure, through stress or exogenous glucocorticoids, results in reduced birthweight, as well as affective and neuropsychiatric outcomes in adults, combined with altered hypothalamus-pituitary-adrenal (HPA) axis activity. As such, glucocorticoids are tightly regulated during development through the presence of the metabolising enzyme 11β-Hydroxysteroid Dehydrogenase type 2 (HSD2). HSD2 is highly expressed in two hubs during development: the placenta and the fetus itself, protecting the fetus from inappropriate glucocorticoid exposure early in gestation. Through manipulation of HSD2 expression in the mouse placenta and fetal tissues, we are able to determine the relative contribution of glucocorticoid exposure in each compartment. Feto-placental HSD2 deletion resulted in reduced birthweight and the development of anxiety- and depression-like behaviours in adult mice. The placenta itself is altered by glucocorticoid overexposure, which causes reduced placental weight and vascular arborisation. Furthermore, altered flow and resistance in the umbilical vessels and modification of fetal heart function and development is observed. However, brain-specific HSD2 removal (HSD2BKO), also generated adult phenotypes of depressive-like behaviour and memory deficit, demonstrating the importance of fetal brain HSD2 expression in development. In this review we will discuss potential mechanisms underpinning early-life programming of adult neuropsychiatric disorders and the novel therapeutic potential of statins.

Original languageEnglish
Pages (from-to)257-265
Number of pages9
Issue number3
Early online date19 Mar 2019
Publication statusPublished - 1 Sep 2019


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