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

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

Research output: Contribution to journalArticle

25 Citations (Scopus)

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
Externally publishedYes

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Fragile X Mental Retardation Protein
Fragile X Syndrome
Knockout Mice
Depression
Protein Isoforms
Central Nervous System
Anisomycin
Phenotype
Dependovirus
Neuronal Plasticity
Excitatory Postsynaptic Potentials
Intellectual Disability
Cognition
Mutation
Injections
Genes
Proteins

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Fragile X mental retardation protein replacement restores hippocampal synaptic function in a mouse model of fragile X syndrome. / Zeier, Zane R; Kumar, A.; Bodhinathan, K.; Feller, J. A.; Foster, T. C.; Bloom, D. C.

In: Gene Therapy, Vol. 16, No. 9, 2009, p. 1122-1129.

Research output: Contribution to journalArticle

Zeier, Zane R ; Kumar, A. ; Bodhinathan, K. ; Feller, J. A. ; Foster, T. C. ; Bloom, D. C. / Fragile X mental retardation protein replacement restores hippocampal synaptic function in a mouse model of fragile X syndrome. In: Gene Therapy. 2009 ; Vol. 16, No. 9. pp. 1122-1129.
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