title: Protease induced plasticity: matrix metalloproteinase-1 promotes neurostructural changes through activation of protease activated receptor 1.
abstract: Matrix metalloproteinases (MMPs) are a family of secreted endopeptidases expressed by neurons and glia. Regulated MMP activity contributes to physiological synaptic plasticity, while dysregulated activity can stimulate injury. Disentangling the role individual MMPs play in synaptic plasticity is difficult due to overlapping structure and function as well as cell-type specific expression. Here, we develop a novel system to investigate the selective overexpression of a single MMP driven by GFAP expressing cells in vivo. We show that MMP-1 induces cellular and behavioral phenotypes consistent with enhanced signaling through the G-protein coupled protease activated receptor 1 (PAR1). Application of exogenous MMP-1, in vitro, stimulates PAR1 dependent increases in intracellular Ca2+concentration and dendritic arborization. Overexpression of MMP-1, in vivo, increases dendritic complexity and induces biochemical and behavioral endpoints consistent with increased GPCR signaling. These data are exciting because we demonstrate that an astrocyte-derived protease can influence neuronal plasticity through an extracellular matrix independent mechanism.
authors.affiliation: Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC, USA.|Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Allen
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Suhasini
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA.|Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Gerard P
authors.initials: GP
authors.lastname: Ahern
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: Villapol
authors.affiliation: Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC, USA.|Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA.|Department of Biology, Georgetown University, Washington, DC, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Maguire-Zeiss
authors.affiliation: Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC, USA.|Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Conant
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001522:Behavior, Animal; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism; D004789:Enzyme Activation; D015870:Gene Expression; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D008279:Magnetic Resonance Imaging; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009457:Neuroglia / Q000378:metabolism; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000819:agonists*; D013569:Synapses / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; D012333:RNA, Messenger; D044463:Receptor, PAR-1; D020781:Matrix Metalloproteinase 1; D002118:Calcium