Elsevier

Neuroscience

Volume 137, Issue 3, 2006, Pages 865-873
Neuroscience

Developmental neuroscience
11β-Hydroxysteroid dehydrogenase type 2 protects the neonatal cerebellum from deleterious effects of glucocorticoids

https://doi.org/10.1016/j.neuroscience.2005.09.037Get rights and content

Abstract

11β-Hydroxysteroid dehydrogenase type 2 is a glucocorticoid metabolizing enzyme that catalyzes rapid inactivation of corticosterone and cortisol to inert 11-keto derivatives. As 11β-hydroxysteroid dehydrogenase type 2 is highly expressed in the developing brain, but not in the adult CNS, we hypothesized that it may represent a protective barrier to the deleterious actions of corticosteroids on proliferating cells. To test this hypothesis we have investigated the development and growth of the cerebellum in neonatal C57BL/6 mice and mice lacking 11β-hydroxysteroid dehydrogenase type 2 (−/−). 11β-Hydroxysteroid dehydrogenase type 2−/− mice had consistently lower body weight throughout the neonatal period, coupled with a smaller brain size although this was normalized when corrected for body weight. The cerebellar size was smaller in 11β-hydroxysteroid dehydrogenase type 2−/− mice, due to decreases in size of both the molecular and internal granule layers. When exogenous corticosterone was administered to the pups between postnatal days 4 and 13, 11β-hydroxysteroid dehydrogenase type 2−/− mice were more sensitive, showing further inhibition of cerebellar growth while the wildtype mice were not affected. Upon withdrawal of exogenous steroid, there was a rebound growth spurt so that at day 21 postnatally, the cerebellar size in 11β-hydroxysteroid ehydrogenase type 2−/− mice was similar to untreated mice of the same genotype. Furthermore, 11β-hydroxysteroid dehydrogenase type 2−/− mice had a delay in the attainment of neurodevelopmental landmarks such as negative geotaxis and eye opening. We therefore suggest that 11β-hydroxysteroid dehydrogenase type 2 acts as to protect the developing nervous system from the deleterious consequences of glucocorticoid overexposure.

Section snippets

Animals

Male and female 11β-HSD2−/− mice (congenic—10 generations—on the C57BL/6J background) were housed in pairs in breeding cages with bedding for nest building. The resulting offspring were compared with offspring from similarly housed C57Bl/6J control mice. The light/dark cycle was kept constant with lights on from 07:00 h to 19:00 h. Animals were given standard chow and water ad libitum, and all studies were carried out to the highest standards of humane care in strict accordance with the UK

Ontogeny of 11β-HSD2 expression in mouse neonatal cerebellum

11β-HSD2 mRNA is highly expressed in the proliferating, EGL of the postnatal cerebellum (Fig. 1). As the EGL decreases in size, the 11β-HSD2 mRNA expression also decreases, until after P14 no detectable expression is observed in the cerebellum throughout the rest of life. In the adult mouse brain high expression of 11β-HSD2 is only seen in the nucleus of the tractus solitarius, an area of the brain involved in blood pressure regulation.

Neonatal morphometry

There was no difference in the litter size or gestation

Discussion

11β-HSD2−/− pups are smaller during early postnatal growth, but overall brain weight is spared throughout. However the cerebellum, a region of the brain which expresses 11β-HSD2 into the postnatal period and is still proliferating at this time, has reduced postnatal growth in 11β-HSD2−/− mice. The reduction in cerebellar size was observed in both the granule and MLs and was coupled with delayed maturation of developmental reflexes.

We have demonstrated that the neonatal growth of the mouse

Conclusion

In conclusion, loss of 11β-HSD2 results in elevated exposure of the developing brain to active glucocorticoids. The consequence of this exposure is a smaller cerebellar size, a greater sensitivity to exogenous corticosterone and delayed developmental landmarks. We, therefore, suggest that 11β-HSD2 acts to protect the developing nervous system against the deleterious consequences of glucocorticoid overexposure which may otherwise result in long-lasting behavioral and functional defects.

Acknowledgments

This work was supported by a project grant from the Wellcome Trust.

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