Genetic Removal of Matrix Metalloproteinase 9 Rescues the Symptoms of Fragile X Syndrome in a Mouse Model

  • Sidhu H
  • Dansie L
  • Hickmott P
 et al. 
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Abstract

Fmr1 knock-out (ko) mice display key features of fragile X syndrome
(FXS), including delayed dendritic spine maturation and FXS-associated
behaviors, such as poor socialization, obsessive-compulsive behavior,
and hyperactivity. Here we provide conclusive evidence that matrix
metalloproteinase-9 (MMP-9) is necessary to the development of
FXS-associated defects in Fmr1 ko mice. Genetic disruption of Mmp-9
rescued key aspects of Fmr1 deficiency, including dendritic spine
abnormalities, abnormal mGluR5-dependent LTD, as well as aberrant
behaviors in open field and social novelty tests. Remarkably, MMP-9
deficiency also corrected non-neural features of Fmr1
deficiency-specifically macroorchidism-indicating that MMP-9
dysregulation contributes to FXS-associated abnormalities outside the
CNS. Further, MMP-9 deficiency suppressed elevations of Akt, mammalian
target of rapamycin, and eukaryotic translation initiation factor 4E
phosphorylation seen in Fmr1 ko mice, which are also associated with
other autistic spectrum disorders. These findings establish that MMP-9
is critical to the mechanisms responsible for neural and non-neural
aspects of the FXS phenotype.

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Authors

  • Harpreet Sidhu

  • Lorraine E Dansie

  • Peter W Hickmott

  • Douglas W Ethell

  • Iryna M Ethell

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