Correction of Fragile X Syndrome in Mice

Gül Dölen, Emily Osterweil, B. S.Shankaranarayana Rao, Gordon B. Smith, Benjamin D. Auerbach, Sumantra Chattarji, Mark F. Bear

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707 Scopus citations

Abstract

Fragile X syndrome (FXS) is the most common form of heritable mental retardation and the leading identified cause of autism. FXS is caused by transcriptional silencing of the FMR1 gene that encodes the fragile X mental retardation protein (FMRP), but the pathogenesis of the disease is unknown. According to one proposal, many psychiatric and neurological symptoms of FXS result from unchecked activation of mGluR5, a metabotropic glutamate receptor. To test this idea we generated Fmr1 mutant mice with a 50% reduction in mGluR5 expression and studied a range of phenotypes with relevance to the human disorder. Our results demonstrate that mGluR5 contributes significantly to the pathogenesis of the disease, a finding that has significant therapeutic implications for fragile X and related developmental disorders.

Original languageEnglish (US)
Pages (from-to)955-962
Number of pages8
JournalNeuron
Volume56
Issue number6
DOIs
StatePublished - Dec 20 2007

Bibliographical note

Funding Information:
We are grateful to M. Shuler for helpful discussion of appropriate statistical analysis; K. Oram, C. Dudley, A. Topolszki, T. Udaka, and C. Poo for genotyping and animal care; E. Sklar for technical assistance and construction of AGS stimulus; M. Frenkel for use of previously published data; S. Meagher for administrative support; A. Kraev and J. Roder for Grm5 genotyping protocols; K. Huber, K. Wiig, A. Govindarajan, R. Paylor, W. Chen, B. Yoon, Q. Yan, R. Bauchwitz, M. Tranfaglia, E. Klann, E. Berry-Kravis, and A. Heynen for helpful discussions. Supported by the NIMH, NICHD, National Fragile X Foundation, FRAXA, Simons Foundation. M.F.B. discloses a financial interest in Seaside Therapeutics.

Keywords

  • HUMDISEASE
  • MOLNEURO

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