As a measure of functional activity we determined regional cerebral metabolic rate for glucose (rCMR(glc)) in adult, female wild type and fragile X (Fmr1 null) mice homozygous and heterozygous for the null mutation. To ascertain if the sexes differ with respect to the severity of the effects of the mutation we compared our results with results of our previous study on male Fmr1 null mice [Qin M, Kang J, Smith CB (2002) Increased rates of cerebral glucose metabolism in a mouse model of fragile X mental retardation. Proc Natl Acad Sci U S A 99:15758-15763.]. In contrast to the male Fmr1 null mouse, rCMR(glc) was unchanged in the homozygous female except in the dorsal raphe where rCMR(glc) was increased by 36%. There were no differences in rCMR(glc) between heterozygous and wild type female mice. We compared male and female mice for effects of the null mutation on behavior. We found that the female Fmr1 null mouse is similar to the male with deficits in performance on a passive avoidance task, general hyperactivity, and increased susceptibility to audiogenic seizures. Both homozygous and heterozygous female mice exhibited hyperactivity and increased susceptibility to seizures, whereas only the homozygous mice had a deficit on the passive avoidance test. Male Fmr1 null mice had a tendency for lower anxiety-like behavior in an open field, whereas this was not evident in females. Compared with male wild type, male Fmr1 null mice also had a diminished acoustic startle response at higher stimulus intensities, whereas all three female genotypes had responses similar to those of male Fmr1 null mice. Whether estrogen affords female Fmr1 null mice some protection from the effects of the mutation remains to be determined.