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 postinjury. 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 Ncadherin 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 Ncadherin 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 pairedpulse 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.

Osteopontin expression in acute immune response mediates hippocampal synaptogenesis and adaptive outcome following cortical brain injury

“…For OPN KOs, 115 kD N-cadherin level was significantly reduced (82.9 ±5.7%; p<0.05), and the 35 kD fragment was highly variable, not different from control levels (105.2 ± 25.4%; p=0.535). Since N-cadherin localizes within ML reactive astrocytes after UEC (Warren et al, 2012), these results are consistent with the hypothesis that reactive glia can mediate the proteolysis of full length N-cadherin to facilitate synaptic reshaping during reactive synaptogenesis.…”

“…At 1 and 2d after UEC (n=4/group), rats were prepared for fluorescent immunohistochemical (IHC) analysis according to published protocol (Warren et al, 2012). Animals were anaesthetized with sodium pentobarbital (90 mg/kg, i.p.…”

“…Importantly, MMP lysis exposes these RGD/SVVYGLR sequences, generating integrin binding OPN fragments which stimulate reactive microglia and astrocytes (Ellison et al, 1998; Shin et al, 2005; Kang et al, 2008). While MMPs alter CNS plasticity in a time dependent fashion (Goussev et al, 2003; Falo et al, 2006; Warren et al, 2012), the significance of such OPN fragment production during synaptogenesis is not understood. This interaction suggests that MMP OPN processing within the synaptogenic environment supports cell signaling for ECM boundary formation, guiding debris clearance and axonal-dendritic regeneration.…”

Enhanced astrocytic d-serine underlies synaptic damage after traumatic brain injury

“…Specialized membranes, such as at synapses, are susceptible to unique environmental changes within the injured brain, where astrocytes in the tripartite synapse contribute to synaptic transmission and function (1)(2)(3). TBI is known to result in astrocyte reactivity, which has both beneficial and deleterious effects on injury progression and recovery; however, few studies have examined the effects of astrogliosis on synaptic stability in the CNS (4)(5)(6).…”

Post-Acute Brain Injury Urinary Signature: A New Resource for Molecular Diagnostics

“…Identified peptides were largely fragments of extracellular matrix (ECM) and membranous proteins that are known to, or may likely, shed peptides during synaptic reorganization. 36,37 Four distinct activity networks of interest were related to outgrowth, guidance and morphogenesis, the ECM, transcriptional activity, and post-synaptic density interaction. This later network included peptides from several major components of the excitatory glutamate receptor complex, including glutamate receptor 2A and B (Grin2A/B), synaptic Ras GTPase activating protein 1(Syngap1), and SH3 ankyrin repeat domain 1 (Shank1).…”