Testosterone down regulates the expression of Fmr-1 gene in the cerebral cortex of gonadectomized old male mice

Sex steroid hormones are important modulators of synaptic plasticity underlying learning and memory, however, the precise molecular mechanism of their role in above is not well understood. Fragile X mental retardation protein is one of the proteins that regulate synaptic plasticity that declines during aging. Whether Fmr-1 gene expression is regulated by sex steroid hormones as a function of age is not known. To answer this, we have investigated Fmr-1 gene expression in the cerebral cortex of the gonadectomized- and testosterone-treated gonadectomized adult and old male mice. Our data reveal that Fmr-1 gene expression is significantly down regulated in adult mice brain, however, it is up regulated in old age following bilateral gonadectomy (castration). Administration of testosterone to castrated mice was found to reverse the effects of castration on Fmr-1 gene expression towards that in the Sham operated intact control old age mice whereas it has no effects as compared to that in Sham operated adult age mice. Further, to investigate the mechanism of this effect of testosterone, we studied interaction of trans-acting factors with Fmr-1 promoter by electrophoretic mobility shift assay (EMSA). The EMSA data shows formation of two complexes as a result of interaction of nuclear trans-acting factors with Fmr-1 promoter, which also exhibited age- and hormone-dependent patterns which largely corresponded to the patterns of our expression data. Our data demonstrate that testosterone regulates Fmr-1 gene expression in age-dependent manner which may throw light on the mechanisms of age- and sex steroid hormones-dependent alterations in brain function.