title: Matrix Metalloproteinase-9 Regulates Neuronal Circuit Development and Excitability.
abstract: In early postnatal development, naturally occurring cell death, dendritic outgrowth, and synaptogenesis sculpt neuronal ensembles into functional neuronal circuits. Here, we demonstrate that deletion of the extracellular proteinase matrix metalloproteinase-9 (MMP-9) affects each of these processes, resulting in maladapted neuronal circuitry. MMP-9 deletion increases the number of CA1 pyramidal neurons but decreases dendritic length and complexity. Parallel changes in neuronal morphology are observed in primary visual cortex and persist into adulthood. Individual CA1 neurons in MMP-9(-/-) mice have enhanced input resistance and a significant increase in the frequency, but not amplitude, of miniature excitatory postsynaptic currents (mEPSCs). Additionally, deletion of MMP-9 significantly increases spontaneous neuronal activity in awake MMP-9(-/-) mice and enhances response to acute challenge by the excitotoxin kainate. Our data document a novel role for MMP-9-dependent proteolysis: the regulation of several aspects of circuit maturation to constrain excitability throughout life.
authors.affiliation: Laboratory of Molecular Biology, National Institute of Neurological Disorder and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA. smurase@umd.edu.|Department of Biology and Neuroscience and Cognitive Sciences Program, University of Maryland, College Park, MD, 20742, USA. smurase@umd.edu.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Murase
authors.affiliation: Department of Biology and Neuroscience and Cognitive Sciences Program, University of Maryland, College Park, MD, 20742, USA.
authors.forename: Crystal L
authors.initials: CL
authors.lastname: Lantz
authors.affiliation: Molecular Neurophysiology and Biophysics Section, Program in Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Kim
authors.affiliation: Laboratory of Cellular and Synaptic Neurophysiology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Nitin
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Department of Biology and Neuroscience and Cognitive Sciences Program, University of Maryland, College Park, MD, 20742, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Higgins
authors.affiliation: Laboratory of Cellular and Synaptic Neurophysiology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Stopfer
authors.affiliation: Molecular Neurophysiology and Biophysics Section, Program in Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Dax A
authors.initials: DA
authors.lastname: Hoffman
authors.affiliation: Department of Biology and Neuroscience and Cognitive Sciences Program, University of Maryland, College Park, MD, 20742, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Quinlan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000378:metabolism; D016923:Cell Death; D049229:Dendritic Spines / Q000378:metabolism / Q000473:pathology; D005260:Female; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D007608:Kainic Acid; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009415:Nerve Net / Q000201:enzymology* / Q000502:physiology*; D009474:Neurons / Q000201:enzymology* / Q000473:pathology / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism / Q000473:pathology; D012640:Seizures / Q000473:pathology / Q000503:physiopathology; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission
chemical_list: D015415:Biomarkers; D016760:Proto-Oncogene Proteins c-fos; D020780:Matrix Metalloproteinase 9; D007608:Kainic Acid
keywords: Cell death; Dendritic morphology; Extracellular matrix; Kainate-induced seizure; Spontaneous activity