Fragile X mental retardation protein replacement restores hippocampal synaptic function in a mouse model of fragile X syndrome

Z. Zeier, A. Kumar, K. Bodhinathan, J. A. Feller, T. C. Foster, D. C. Bloom

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1122-1129
Number of pages8
JournalGene Therapy
Volume16
Issue number9
DOIs
StatePublished - 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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