title: Elevation of hippocampal MMP-3 expression and activity during trauma-induced synaptogenesis.
abstract: The matrix metalloproteinase (MMP) enzyme family contributes to the regulation of a variety of brain extracellular matrix molecules. In order to assess their role in synaptic plasticity following traumatic brain injury (TBI), we compared expression of stromelysin-1 (MMP-3) protein and mRNA in two rodent models of TBI exhibiting different levels of recovery: adaptive synaptic plasticity following central fluid percussion injury and maladaptive synaptic plasticity generated by combined TBI and bilateral entorhinal cortical lesion (TBI + BEC). We sampled the hippocampus at 7 days postinjury, targeting a selectively vulnerable brain region and a survival interval exhibiting rapid synaptogenesis. We report elevated expression of hippocampal MMP-3 mRNA and protein after TBI. MMP-3 immunohistochemical staining showed increased protein levels relative to sham-injured controls, primarily localized to cell bodies within the deafferented dendritic laminae. Injury-related differences in MMP-3 protein were also observed. TBI alone elevated MMP-3 immunobinding over the stratum lacunosum moleculare (SLM), inner molecular layer and hilus, while TBI + BEC generated more robust increases in MMP-3 reactivity within the deafferented SLM and dentate molecular layer (DML). Double labeling with GFAP confirmed the presence of MMP-3 within reactive astrocytes induced by each injury model. Semi-quantitative RT-PCR revealed that MMP-3 mRNA also increased after each injury, however, the combined insult induced a much greater elevation than fluid percussion alone: 1.9-fold vs. 79%, respectively. In the TBI + BEC model, MMP-3 up-regulation was spatio-temporally correlated with increased enzyme activity, an effect which was attenuated with the neuroprotective compound MK-801. These results show that distinct pathological conditions elicited by TBI can differentially affect MMP-3 expression during reactive synaptic plasticity. Notably, these effects are both transcriptional and translational and are correlated with functionally active enzyme.
authors.affiliation: Department of Anatomy and Neurobiology, School of Medicine, Virginia Commonwealth University Medical Center, Medical Sciences Building Room #736, 1217 E. Marshall Street, PO Box 980709, Richmond, VA 23298, USA.
authors.forename: H J
authors.initials: HJ
authors.lastname: Kim
authors.forename: H L
authors.initials: HL
authors.lastname: Fillmore
authors.forename: T M
authors.initials: TM
authors.lastname: Reeves
authors.forename: L L
authors.initials: LL
authors.lastname: Phillips
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000201:enzymology; D001930:Brain Injuries / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D003714:Denervation / Q000009:adverse effects; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018728:Entorhinal Cortex / Q000293:injuries / Q000503:physiopathology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D006624:Hippocampus / Q000201:enzymology* / Q000293:injuries* / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism*; D009434:Neural Pathways / Q000293:injuries / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000201:enzymology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D005904:Glial Fibrillary Acidic Protein; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D016291:Dizocilpine Maleate; D019278:Matrix Metalloproteinase 3