ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2011) 25 OC5.5

Absence of 11[beta]-HSD2 specifically within the fetal brain alters adult 'depressive' behaviour

Caitlin Wyrwoll, Jonathan Seckl & Megan Holmes

The University of Edinburgh, Edinburgh, UK.

Prenatal glucocorticoid overexposure is a key risk factor for susceptibility to neuropsychiatric disorders in adult life. Fetal exposure to glucocorticoids is regulated by 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) an enzyme which inactivates glucocorticoids and is highly expressed in the placenta and fetus. Previous work has established that 11β-HSD2−/− offspring generated by heterozygous matings exhibit altered placental development and function, decreased birth weight, delayed neurodevelopment and increased anxiety and depression as adults. This raises the question as to whether it is placental or fetal 11β-HSD2 that are key to subsequent programmed outcomes. The current study investigated the significance of neural 11β-HSD2 on adult behaviour. A knockout of 11β-HSD2 specifically within the brain during development was created by crossing NestinCre mice with floxed 11β-HSD2 mice (HSD2flx/flx). 11β-HSD2 activity in fetal tissue and placenta was measured at E12.5, neurodevelopmental landmarks assessed and adult behaviour characterised. Brain-specific reduction in 11β-HSD2 activity was confirmed at E12.5 in the fetal heads of NestinCre.HSD2flx/flx mice in comparison to HSD2flx/flx (2.01±0.24 and 10.13±1.69 nmol A/mg per hour respectively, P<0.01). Birth weight and negative geotaxis and eye opening, markers of neurodevelopment, were unaltered. Anxiety was assessed by elevated plus maze and open field in the adult offspring and was unchanged between the two genotypes. However depressive-like behaviour, as assessed by the tail suspension test, was increased in mice with brain-specific deletion of 11β-HSD2 with NestinCre.HSD2flx/flx spending a greater percentage of time hanging in comparison to the HSD2flx/flx mice (68 and 53% respectively, P<0.05). Our data suggest that neural 11β-HSD2 does indeed have a role in protecting the developing brain and thus determining adult psychiatry. However this may prove to be a minor role compared to that of 11β-HSD2 in the placenta as the current observed phenotype appears more subtle than the global 11β-HSD2 knockout.

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