title: MT5-MMP, ADAM-10, and N-cadherin act in concert to facilitate synapse reorganization after traumatic brain injury.
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.
authors.affiliation: Department of Anatomy and Neurobiology, School of Medicine, Virginia Commonwealth University Medical Center, Richmond, VA 23298, USA.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Warren
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Reeves
authors.forename: Linda L
authors.initials: LL
authors.lastname: Phillips
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000502:physiology*; D000072197:ADAM10 Protein; D000818:Animals; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015820:Cadherins / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D008297:Male; D053504:Matrix Metalloproteinases, Membrane-Associated / Q000235:genetics / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000502:physiology* / Q000648:ultrastructure
chemical_list: D015820:Cadherins; C570099:N-cadherin, rat; D009419:Nerve Tissue Proteins; D051722:ADAM Proteins; D053504:Matrix Metalloproteinases, Membrane-Associated; C492242:Mmp24 protein, rat; D000072197:ADAM10 Protein; C542371:ADAM10 protein, rat