Abstracts

Rationale: In Fragile-X Syndrome (FXS), mutations in the Fmr1 gene result in reduced levels of Fragile-X Mental Retardation Protein (FMRP). FMRP binds to select mRNAs and suppresses their translation. We have demonstrated that FMRP binds to STriatal-Enriched protein tyrosine Phosphatase (STEP) and that STEP protein is upregulated in Fmr1 KO mice. These findings suggest that STEP translation is regulated by FMRP. STEP mediates the trafficking of NMDA and AMPA receptors and participates in metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD). It is also well-established that Fmr1 KO mice are susceptible to audiogenic seizures. Here we show that STEP levels are linked to the susceptibility of Fmr1 KO mice to audiogenic seizures. Methods: We genetically reduced STEP levels in Fmr1 KO mice by crossing STEP KO mice with Fmr1 KO mice. To determined whether decreasing STEP levels reduced audiogenic seizures in Fmr1 KO mice, we compared seizure frequency and severity in WT, Fmr1 KO, Fmr1 KO/STEP Het, and Fmr1 KO/STEP KO mice (PND21-24). Mice were subjected to an auditory stimulus of variable frequency at 125-130dB at a distance of 0.6m. Results: We found that STEP levels correlated with seizure-related activity in a dose-dependent manner. Fmr1 KO/STEP Het mice showed a high incidence of audiogenic seizures, as predicted from prior studies. By contrast, Fmr1 KO/STEP KO mice were resistant to audiogenic seizures. Conclusions: These findings suggest that therapies to reduce STEP levels in individuals with Fragile X syndrome may be anti-convulsant.