The role of 11beta-hydroxysteroid dehydrogenases in the brain.

Glucocorticoids have a plethora of effects within the body to maintain homeostasis. In the brain they modify learning, memory and fear behaviours as well as regulating their own secretion by a negative feedback action. 11Beta-hydroxysteroid dehydrogenases (11beta-HSDs) are glucocorticoid metabolising enzymes that modify actions of glucocorticoids in a tissue specific manner. 11Beta-HSD1 regenerates active glucocorticoids from their inactive 11-keto derivatives, hence boosting tissue levels of corticosterone and cortisol. Removal of this enzyme (11beta-HSD1-/- mice) results in apparent lower intra-hippocampal corticosterone levels and reduces glucocorticoid-associated cognitive decline during ageing. This low corticosterone tissue environment is maintained even though there is a hyperactive hypothalamic-pituitary-adrenal axis and elevated basal and stress-induced plasma corticosterone levels. Conversely, the major central effects of 11beta-HSD2 are seen in development, as expression of 11beta-HSD2 is high in fetal and certain parts of the neonate brain, but is confined to a few discrete regions of the adult brain. 11Beta-HSD2 acts as a dehydrogenase, inactivating corticosterone or cortisol through conversion to 11-dehydrocorticosterone and cortisone. Loss of 11beta-HSD2 from the fetus and fetally derived tissues results in altered development of the cerebellum in the neonatal period and a life-long phenotype of anxiety, consistent with early life glucocorticoid programming.