Endocrine Abstracts

Glucocorticoids have profound effects in development, altering cell proliferation, differentiation, migration and network formation. It has been shown that the developing fetus is protected from high maternal glucocorticoid levels by the presence of 11beta-HSD2 in the placenta and if this enzyme is inhibited, programmed changes of adult health are observed (hypertension, hyperglycaemia, insulin resistance). The developing brain is a sensitive target for glucocorticoids and hence a second barrier to their action is expression of 11beta-HSD2 in proliferating areas of the brain. We have used transgenic mice lacking expression of 11beta-HSD2 (11beta-HSD2 ko) to determine the consequences of enzyme loss on markers of brain development and behaviour. Data are given as mean plus/minus SEM. Consistent with elevated corticosterone levels reaching the fetus, the mice have decreased birth weight (1.34 plus/minus 0.028g in C57BL/6 (WT) mice compared to 1.21 plus/minus 0.028g in 11beta-HSD2 ko mice; p less than 0.05) and decreased postnatal growth of the cerebellum, an area of the brain still proliferating postnatally, regulated by glucocorticoids and normally protected by expression of 11beta-HSD2 in the proliferating external granule layer. At postnatal day (P)21, the midsagittal area of the cerebellum was reduced by 15% in the 11beta-HSD2 ko mice compared to WT controls. The reduced cerebellar size in the 11beta-HSD2 ko mice does not appear to be due to different neuronal proliferation rates as determined by BrDU incorporation at P7 and P14. Two developmental markers (righting reflex and eyes opening) are delayed in the 11beta-HSD2 ko mice; 50% less 11beta-HSD2 ko mice being able to turn at P7 compared to WT. As adults, these mice develop an anxious phenotype assessed by the elevated plus maze (57% decrease in open arm entries), which is consistent with the glucocorticoid programming observed in the rat. These results confirm the importance of 11beta-HSD2 as a protector from maternal glucocorticoids in the developing brain. This work was supported by the Wellcome Trust.