title: Osteopontin expression in acute immune response mediates hippocampal synaptogenesis and adaptive outcome following cortical brain injury.
abstract: Traumatic brain injury (TBI) produces axotomy, deafferentation and reactive synaptogenesis. Inflammation influences synaptic repair, and the novel brain cytokine osteopontin (OPN) has potential to support axon regeneration through exposure of its integrin receptor binding sites. This study explored whether OPN secretion and proteolysis by matrix metalloproteinases (MMPs) mediate the initial degenerative phase of synaptogenesis, targeting reactive neuroglia to affect successful repair. Adult rats received unilateral entorhinal cortex lesion (UEC) modeling adaptive synaptic plasticity. Over the first week postinjury, hippocampal OPN protein and mRNA were assayed and histology was performed. At 1-2d, OPN protein increased up to 51 fold, and was localized within activated, mobilized glia. OPN transcript also increased over 50 fold, predominantly within reactive microglia. OPN fragments known to be derived from MMP proteolysis were elevated at 1d, consistent with prior reports of UEC glial activation and enzyme production. Postinjury minocycline immunosuppression attenuated MMP-9 gelatinase activity, which was correlated with the reduction of neutrophil gelatinase-associated lipocalin (LCN2) expression, and reduced OPN fragment generation. The antibiotic also attenuated removal of synapsin-1 positive axons from the deafferented zone. OPN KO mice subjected to UEC had similar reduction of hippocampal MMP-9 activity, as well as lower synapsin-1 breakdown over the deafferented zone. MAP1B and N-cadherin, surrogates of cytoarchitecture and synaptic adhesion, were not affected. OPN KO mice with UEC exhibited time dependent cognitive deficits during the synaptogenic phase of recovery. This study demonstrates that OPN can mediate immune response during TBI synaptic repair, positively influencing synapse reorganization and functional recovery.
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University, P.O. Box 980709, Richmond, VA 23298, USA.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Chan
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University, P.O. Box 980709, Richmond, VA 23298, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Reeves
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University, P.O. Box 980709, Richmond, VA 23298, USA. Electronic address: llphilli@vcu.edu.
authors.forename: Linda L
authors.initials: LL
authors.lastname: Phillips
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000276:immunology* / Q000473:pathology*; D002540:Cerebral Cortex / Q000473:pathology; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D007839:Functional Laterality / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008911:Minocycline / Q000494:pharmacology; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D021641:Recognition, Psychology / Q000187:drug effects; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D053495:Osteopontin; D020784:Matrix Metalloproteinase 8; D008911:Minocycline