Fragile X Syndrome (FXS) is the most common form of inherited mental retardation and results from the silencing of the Fmr1 gene that encodes the Fragile X Mental Retardation Protein (FMRP). FMRP binds the mRNA for the glucocorticoid receptor, expression of which is reduced in apical dendrites of CA1 pyramidal neurons (Neuron 37:417-31). The hippocampus is involved in the negative feedback loop regulating the stress response, and the response to acute stress is elevated in children with FXS (PNEC 27:855-72;J Dev Behav Pediatr 21:278-82). Here we confirm our preliminary finding that Fmr1 null mice have a prolonged elevation of serum glucocorticoid in response to an acute stressor (SFN’03, #646.5) and report that the stress response of the KO mouse varies according to sex. Male and female (40-45 days) Fmr1 KO and WT control mice (N13C57Bl/6) were exposed to 30 min. of acute restraint stress. Serum corticosterone levels were assayed from unstressed animals and those examined either immediately following stres...