Journal
GENE THERAPY
Volume 16, Issue 9, Pages 1122-1129Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gt.2009.83
Keywords
fragile X syndrome; FMRP; FMR1; AAV; hippocampus; LTD
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Funding
- National Institutes of Health [AG14979, MH059891]
- Evelyn F. McKnight Brain Research
- University of Florida Alumni Fellowship
- FRAXA Research Foundation
- Burroughs Wellcome Fund
- NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH059891] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG014979] Funding Source: NIH RePORTER
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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 whether FMRP replacement can rescue phenotypic deficits in a fmr1-knockout (KO) mouse model of FXS, we constructed an adeno-associated virus-based viral vector that expresses the major central nervous system (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 (WT) 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 WT 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 WT 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. Gene Therapy (2009) 16, 1122-1129; doi: 10.1038/gt.2009.83; published online 2 July 2009
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