The extent of long-term functional recovery following traumatic brain injury (TBI) is clearly associated with the capacity for adaptive synaptic plasticity within injured circuitry. Recent evidence supports a role for extracellular matrix proteins (ECMs) and their regulatory metalloproteinases (MMPs) in neurite growth and synaptic reorganization after CNS trauma. Given that these molecules are found within brain regions vulnerable to TBI, we have begun to examine members of the gelatinase and stromelysin MMP families during injury-induced synaptic plasticity. We hypothesize that the interaction of MMPs and their ECM substrates during synaptic reorganization determines the success of long-term recovery following TBI. Specifically, we posit that MMPs control ECM dissociation during removal of degenerating terminals, and subsequently regulate distribution of ECM associated molecules involved with synaptogenesis. Our approach will first identify the spatio-temporal pattern of MMP expression and functional activity after unilateral entorhinal lesion (UEC), an insult which induces the well-defined process of reactive synaptogenesis within the hippocampus. The neuronal plasticity induced in this model results in adaptive restoration of synaptic structure and function. With the UEC pattern as a baseline for comparison, we will profile MMP expression and function after brain trauma using the rat TBI model which combines excessive neuroexcitation of percussive injury with targeted hippocampal deafferentation of entorhinal lesion (TBI+BEC insult). We have shown that this model reliably produces a persistent, maladaptive synaptic plasticity and severe long-term cognitive deficits. Initially, we will examine both protein (LM/EM immunohistochemistry, Western blots) and mRNA (RT-PCR, Northern blot and/or in situ hybridization) expression for select MMPs (gelatinases A and B; stromelysin) and their associated ECM substrates (collagenase IV, chondroitin sulfated proteoglycan, enascin) after injury. Additional experiments will determine how effects on protein and mRNA are correlated with MMP enzyme activity (gel zymography and chromogenic enzyme assay). Next, we will establish whether these injury-induced changes in MMPs/ECMs are associated with alterations in electrophysiological measures of synaptic plasticity (LTP, paired-pulse facilitation, current-source-density analysis) and changes in cognitive outcome (Morris Water Maze performance). Finally we will test the association between MMPs and synaptic reorganization following TBI by: 1) applying specific MMP inhibitors and assessing the extent of synaptic plasticity generated, and 2) enhancing injury-induced plasticity with compounds targeting NMDA and dopamine receptors and then assessing MMP expression and functional activity. Together, these studies will establish whether or not MMPs play a role in regenerative processes evoked by TBI and potentially identify novel therapies for brain trauma victims.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS044372-01
Application #
6522074
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Michel, Mary E
Project Start
2002-05-15
Project End
2007-04-30
Budget Start
2002-05-15
Budget End
2003-04-30
Support Year
1
Fiscal Year
2002
Total Cost
$341,003
Indirect Cost
Name
Virginia Commonwealth University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
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Sato, Masatoshi; Sagawa, Yohei; Hirai, Nobuhide et al. (2014) Noninvasive detection of sleep/wake changes and cataplexy-like behaviors in orexin/ataxin-3 transgenic narcoleptic mice across the disease onset. Exp Neurol 261:744-51
Phillips, Linda L; Chan, Julie L; Doperalski, Adele E et al. (2014) Time dependent integration of matrix metalloproteinases and their targeted substrates directs axonal sprouting and synaptogenesis following central nervous system injury. Neural Regen Res 9:362-76
Chan, Julie L; Reeves, Thomas M; Phillips, Linda L (2014) Osteopontin expression in acute immune response mediates hippocampal synaptogenesis and adaptive outcome following cortical brain injury. Exp Neurol 261:757-71
Warren, Kelly M; Reeves, Thomas M; Phillips, Linda L (2012) MT5-MMP, ADAM-10, and N-cadherin act in concert to facilitate synapse reorganization after traumatic brain injury. J Neurotrauma 29:1922-40
Harris, Janna L; Reeves, Thomas M; Phillips, Linda L (2011) Phosphacan and receptor protein tyrosine phosphatase ýý expression mediates deafferentation-induced synaptogenesis. Hippocampus 21:81-92
Harris, Janna L; Reeves, Thomas M; Phillips, Linda L (2009) Injury modality, survival interval, and sample region are critical determinants of qRT-PCR reference gene selection during long-term recovery from brain trauma. J Neurotrauma 26:1669-81
Reeves, Thomas M; Phillips, Linda L; Lee, Nancy N et al. (2007) Preferential neuroprotective effect of tacrolimus (FK506) on unmyelinated axons following traumatic brain injury. Brain Res 1154:225-36