Developmental neuroscience11β-Hydroxysteroid dehydrogenase type 2 protects the neonatal cerebellum from deleterious effects of glucocorticoids
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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