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- Title
Fragile X mental retardation protein replacement restores hippocampal synaptic function in a mouse model of fragile X syndrome.
- Authors
Zeier, Z.; Kumar, A.; Bodhinathan, K.; Feller, J. A.; Foster, T. C.; Bloom, D. C.
- Abstract
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.
- Subjects
INTELLECTUAL disabilities; X chromosome abnormalities; PROTEINS; COGNITION disorders; CENTRAL nervous system diseases; GENOTYPE-environment interaction
- Publication
Gene Therapy, 2009, Vol 16, Issue 9, p1122
- ISSN
0969-7128
- Publication type
Article
- DOI
10.1038/gt.2009.83