Dexamethasone selectively suppresses microglial trophic responses to hippocampal deafferentation

Abstract

Hippocampal deafferentation increases the expression of insulin-like growth factor-1 by microglia, and of ciliary neurotrophic factor and basic fibroblast growth factor by astroglia in fields and periods of reactive axonal growth. Glucocorticoids attenuate lesion-induced hippocampal sprouting, possibly by reducing trophic signals that stimulate growth. With an interest in this hypothesis, the present studies evaluated the influence of systemic treatment with the synthetic glucocorticoid dexamethasone on entorhinal lesion-induced increases in neurotrophic factor expression in young adult rat hippocampus. Daily dexamethasone injections almost completely blocked increases in insulin-like growth factor-1 messenger RNA content, but did not perturb increases in ciliary neurotrophic factor or basic fibroblast growth factor messenger RNA content, in the deafferented dentate gyrus molecular layer. To determine if the suppression of insulin-like growth factor-1 expression was secondary to a general inhibition of microglial responses, and to identify the time period of glucocorticoid sensitivity, additional rats were prepared to evaluate the effects of semi-chronic (i.e. daily) and single dexamethasone injections on microglial proliferation, ED-1 immunoreactivity (a marker of microglial reactivity) and insulin-like growth factor-1 messenger RNA expression. Semi-chronic dexamethasone treatment attenuated all three measures of deafferentation-induced microglial reactivity. However, a single dexamethasone injection given two (but not one or three) days postlesion inhibited deafferentation-induced increases in insulin-like growth factor-1 messenger RNA content, without having significant effects on other measures. These results demonstrate that dexamethasone treatment preferentially suppresses microglial, as opposed to astroglial, trophic responses to deafferentation, and suggest that glucocorticoids attenuate reactive axonal sprouting by inhibiting the microglial production of insulin-like growth factor-1.