FRAGILE X MENTAL RETARDATION PROTEIN REPLACEMENT RESTORES HIPPOCAMPAL SYNAPTIC FUNCTION IN A MOUSE MODEL OF FRAGILE X SYNDROME

Fragile X Syndrome (FXS) is caused by a mutation that silences the Fragile X Mental Retardation gene (FMR1) which encodes the Fragile X Mental Retardation Protein (FMRP). To determine if FMRP replacement can rescue phenotypic deficits in an fmr1 knockout (KO) mouse model of FXS, we constructed an Adeno-Associated Virus-based viral vector that expresses the major CNS isoform of FMRP. Using this vector we tested whether FMRP replacement could rescue the fmr1 KO phenotype of enhanced long-term-depression (LTD), a form of synaptic plasticity that may be linked to cognitive impairments associated with FXS. Extracellular excitatory postsynaptic field potentials were recorded from CA3-CA1 synaptic contacts in hippocampal slices from wild-type and fmr1 KO mice in the presence of AP-5 and anisomycin. Paired-pulse low frequency stimulation (PP-LFS) induced LTD is enhanced in slices obtained from fmr1 KO compared with wild-type mice. Analyses of hippocampal synaptic function in fmr1 KO mice that received hippocampal injections of vector showed that the PP-LFS induced LTD was restored to wild-type levels. These results indicate that expression of the major CNS isoform of FMRP alone is sufficient to rescue this phenotype and suggest that post-developmental protein replacement may have the potential to improve cognitive function in FXS.