MT5-MMP, ADAM-10, and N-cadherin act in concert to facilitate synapse reorganization after traumatic brain injury

J Neurotrauma. 2012 Jul 1;29(10):1922-40. doi: 10.1089/neu.2012.2383. Epub 2012 May 14.

Abstract

Matrix metalloproteinases (MMPs) influence synaptic recovery following traumatic brain injury (TBI). Membrane type 5-matrix metalloproteinase (MT5-MMP) and a distintegrin and metalloproteinase-10 (ADAM-10) are membrane-bound MMPs that cleave N-cadherin, a protein critical to synapse stabilization. This study examined protein and mRNA expression of MT5-MMP, ADAM-10, and N-cadherin after TBI, contrasting adaptive and maladaptive synaptogenesis. The effect of MMP inhibition on MT5-MMP, ADAM-10, and N-cadherin was assessed during maladaptive plasticity and correlated with synaptic function. Rats were subjected to adaptive unilateral entorhinal cortical lesion (UEC) or maladaptive fluid percussion TBI+bilateral entorhinal cortical lesion (TBI+BEC). Hippocampal MT5-MMP and ADAM-10 protein was significantly elevated 2 and 7 days post-injury. At 15 days after UEC, each MMP returned to control level, while TBI+BEC ADAM-10 remained elevated. At 2 and 7 days, N-cadherin protein was below control. By the 15-day synapse stabilization phase, UEC N-cadherin rose above control, a shift not seen for TBI+BEC. At 7 days, increased TBI+BEC ADAM-10 transcript correlated with protein elevation. UEC ADAM-10 mRNA did not change, and no differences in MT5-MMP or N-cadherin mRNA were detected. Confocal imaging showed MT5-MMP, ADAM-10, and N-cadherin localization within reactive astrocytes. MMP inhibition attenuated ADAM-10 protein 15 days after TBI+BEC and increased N-cadherin. This inhibition partially restored long-term potentiation induction, but did not affect paired-pulse facilitation. Our results confirm time- and injury-dependent expression of MT5-MMP, ADAM-10, and N-cadherin during reactive synaptogenesis. Persistent ADAM-10 expression was correlated with attenuated N-cadherin level and reduced functional recovery. MMP inhibition shifted ADAM-10 and N-cadherin toward adaptive expression and improved synaptic function.

Publication types

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

MeSH terms

  • ADAM Proteins / genetics
  • ADAM Proteins / physiology*
  • ADAM10 Protein
  • Animals
  • Brain Injuries / metabolism*
  • Brain Injuries / pathology
  • Brain Injuries / physiopathology
  • Cadherins / genetics
  • Cadherins / physiology*
  • Disease Models, Animal
  • Drug Therapy, Combination
  • Male
  • Matrix Metalloproteinases, Membrane-Associated / genetics
  • Matrix Metalloproteinases, Membrane-Associated / physiology*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology*
  • Neuronal Plasticity / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Synapses / physiology*
  • Synapses / ultrastructure

Substances

  • Cadherins
  • N-cadherin, rat
  • Nerve Tissue Proteins
  • ADAM Proteins
  • Matrix Metalloproteinases, Membrane-Associated
  • Mmp24 protein, rat
  • ADAM10 Protein
  • ADAM10 protein, rat