title: Genetic removal of matrix metalloproteinase 9 rescues the symptoms of fragile X syndrome in a mouse model.
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.
authors: Division of Biomedical Sciences, School of Medicine, and Neuroscience Graduate Program, and.
authors: Harpreet
authors: H
authors: Sidhu
authors: Division of Biomedical Sciences, School of Medicine, and Neuroscience Graduate Program, and.
authors: Lorraine E
authors: LE
authors: Dansie
authors: Department of Psychology, University of California Riverside, Riverside, California 92521, and.
authors: Peter W
authors: PW
authors: Hickmott
authors: Department of Molecular Neurobiology, the Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, California 91766 iryna.ethell@ucr.edu dougeth64@gmail.com.
authors: Douglas W
authors: DW
authors: Ethell
authors: Division of Biomedical Sciences, School of Medicine, and Neuroscience Graduate Program, and iryna.ethell@ucr.edu dougeth64@gmail.com.
authors: Iryna M
authors: IM
authors: Ethell
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005600:Fragile X Syndrome / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D010641:Phenotype
chemical_list: D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: dendritic spines; extracellular matrix; fragile X syndrome; hippocampus; mTOR signaling; matrix metalloproteinase