Matrix Metalloproteinase-9 Regulates Neuronal Circuit Development and Excitability

Mol Neurobiol. 2016 Jul;53(5):3477-3493. doi: 10.1007/s12035-015-9295-y. Epub 2015 Jun 21.


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.

Keywords: Cell death; Dendritic morphology; Extracellular matrix; Kainate-induced seizure; Spontaneous activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Biomarkers / metabolism
  • Cell Death
  • Dendritic Spines / metabolism
  • Dendritic Spines / pathology
  • Female
  • Hippocampus / pathology
  • Hippocampus / physiopathology
  • Kainic Acid
  • Male
  • Matrix Metalloproteinase 9 / deficiency
  • Matrix Metalloproteinase 9 / metabolism*
  • Mice, Inbred C57BL
  • Nerve Net / enzymology*
  • Nerve Net / physiology*
  • Neurons / enzymology*
  • Neurons / pathology
  • Neurons / physiology*
  • Proto-Oncogene Proteins c-fos / metabolism
  • Pyramidal Cells / metabolism
  • Pyramidal Cells / pathology
  • Seizures / pathology
  • Seizures / physiopathology
  • Synapses / metabolism
  • Synaptic Transmission


  • Biomarkers
  • Proto-Oncogene Proteins c-fos
  • Matrix Metalloproteinase 9
  • Kainic Acid