Matrix metalloproteinase-7 modulates synaptic vesicle recycling and induces atrophy of neuronal synapses.
Matrix metalloproteinase-7 (MMP-7) belongs to a family of zinc dependent endopeptidases that are expressed in a variety of tissues including the brain. MMPs are known to be potent mediators of pericellular proteolysis and likely mediators of dynamic remodelling of neuronal connections. While an association between proteases and the neuronal synapse is emerging, a full understanding of this relationship is lacking. Here, we show that MMP-7 alters the structure and function of presynaptic terminals without affecting neuronal survival. Bath application of recombinant MMP-7 to cultured rat neurons induced long-lasting inhibition of vesicular recycling as measured by synaptotagmin 1 antibody uptake assays and FM4-64 optical imaging. MMP-7 application resulted in reduced abundance of vesicular and active zone proteins locally within synaptic terminals although their general levels remained unaltered. Finally, chronic application of the protease resulted in synaptic atrophy, including smaller terminals and fewer synaptic vesicles, as determined by electron microscopy. Together these results suggest that MMP-7 is a potent modulator of synaptic vesicle recycling and synaptic ultrastructure and that elevated levels of the enzyme, as may occur with brain inflammation, may adversely influence neurotransmission.
Szklarczyk
A
A
Laboratory of Systems Neuroscience, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA. aszklar1@jhmi.edu
Conant
K
K
Owens
D F
DF
Ravin
R
R
McKay
R D
RD
Gerfen
C
C
D000818:Animals; D001284:Atrophy; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000494:pharmacology; D020783:Matrix Metalloproteinase 7 / Q000494:pharmacology*; D016253:Microscopy, Immunoelectron / Q000379:methods; D009474:Neurons / Q000187:drug effects*; D021381:Protein Transport / Q000187:drug effects; D011726:Pyridinium Compounds; D000644:Quaternary Ammonium Compounds; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects* / Q000473:pathology*; D013572:Synaptic Vesicles / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D016708:Synaptophysin / Q000378:metabolism; D050863:Synaptotagmin I / Q000378:metabolism; D050988:Vesicle-Associated Membrane Protein 2 / Q000378:metabolism