Abstracts

Rationale: The absence or decrease in the hippocampal expression of Fragile X Mental Retardation Protein (FMRP) has been implicated in the development of seizures in patients with Fragile X syndrome and experimentally after exposure to metabotropic glutamate agonists. Many studies that examine seizure threshold in mice focus on the susceptibility to audiogenic seizures induced at 3 weeks of age. In this study we determined the developmental expression of FMRP in the brains of FVB and C57BL/6J mice, determined the threshold for pilocarpine-induced status epilepticus (SE) in each strain at 3 weeks of age and whether differences in threshold correspond to differences in FMRP expression. Methods: The developmental expression of FMRP was measured in the hippocampus, neocortex, cerebellum and brainstem of male FVB and C57BL/6J mice. Mouse pups (n=4) born to timed-pregnant dams were sacrificed at 3,7,10 and 14 weeks of age. All animals examined at each time point were selected from different litters. Once the brains were removed they were dissected on ice into different regions, homogenized and FMRP expression was measured using the antibody capture Luminex assay. To determine the threshold for the induction of SE, mice at 3 weeks of age from both strains were pretreated with atropine methyl bromide (1mg/kg, ip) followed 30 min later with an injection of pilocarpine (250-365mg/kg, ip). Results: There was no significant difference in the developmental expression of FMRP between the two strains in any of the structures examined at any of the time points examined. At 3 weeks there was a differential expression of FMRP between each structure: cerebellum > neocortex > hippocampus > brainstem. In each strain there was a decrease in FMRP expression in both the hippocampus and cerebellum from age 3-14 weeks. FMRP expression in the brainstem remained stable while a decrease in FMRP expression in the neocortex did not appear until week 14. Although there no significant difference in FMRP expression between the two strains in any of the brain regions examined at 3 weeks of age the threshold for pilocarpine-induced SE was lower in the FVB strain. The threshold for induction of SE at 3 weeks: FVB - 280mg/kg (n=6); C57BK/6J - 310mg/kg (n=11). Conclusions: These results demonstrate that although the absence of FMRP expression can be proepileptogenic the observed difference in seizure susceptibility between the FVB and C57BL/6J mouse strains is not due to a difference in FMRP expression. We did observe differential expression of FMRP across the different structures examined. The difference in seizure susceptibility to audiogenic seizures between the two strains present at 3 weeks of age (Yan et al., Neuropharmacology 49:1053-1066, 2005) is also present for pilocarpine-induced SE. Funding: Supported by NYS OPWDD