A normal genetic variation modulates synaptic MMP-9 protein levels and the severity of schizophrenia symptoms

EMBO Mol Med. 2017 Aug;9(8):1100-1116. doi: 10.15252/emmm.201707723.


Matrix metalloproteinase 9 (MMP-9) has recently emerged as a molecule that contributes to pathological synaptic plasticity in schizophrenia, but explanation of the underlying mechanisms has been missing. In the present study, we performed a phenotype-based genetic association study (PGAS) in > 1,000 schizophrenia patients from the Göttingen Research Association for Schizophrenia (GRAS) data collection and found an association between the MMP-9 rs20544 C/T single-nucleotide polymorphism (SNP) located in the 3'untranslated region (UTR) and the severity of a chronic delusional syndrome. In cultured neurons, the rs20544 SNP influenced synaptic MMP-9 activity and the morphology of dendritic spines. We demonstrated that Fragile X mental retardation protein (FMRP) bound the MMP-9 3'UTR We also found dramatic changes in RNA structure folding and alterations in the affinity of FMRP for MMP-9 RNA, depending on the SNP variant. Finally, we observed greater sensitivity to psychosis-related locomotor hyperactivity in Mmp-9 heterozygous mice. We propose a novel mechanism that involves MMP-9-dependent changes in dendritic spine morphology and the pathophysiology of schizophrenia, providing the first mechanistic insights into the way in which the single base change in the MMP-9 gene (rs20544) influences gene function and results in phenotypic changes observed in schizophrenia patients.

Keywords: Fragile X mental retardation protein; dendritic spine morphology; matrix metalloproteinase 9; phenotype‐based genetic association study; single‐nucleotide polymorphism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Adolescent
  • Adult
  • Aged
  • Animals
  • Cells, Cultured
  • Chronic Disease
  • Disease Models, Animal
  • Female
  • Fragile X Mental Retardation Protein / metabolism
  • Genetic Association Studies
  • Humans
  • Male
  • Matrix Metalloproteinase 9 / analysis*
  • Matrix Metalloproteinase 9 / genetics*
  • Mice
  • Middle Aged
  • Neurons / cytology
  • Nucleic Acid Conformation
  • Polymorphism, Single Nucleotide*
  • Protein Binding
  • RNA, Messenger / chemistry
  • RNA, Messenger / metabolism
  • Schizophrenia, Paranoid / pathology*
  • Synapses / enzymology*
  • Young Adult


  • 3' Untranslated Regions
  • FMR1 protein, human
  • RNA, Messenger
  • Fragile X Mental Retardation Protein
  • Matrix Metalloproteinase 9