title: Association Between Microglia, Inflammatory Factors, and Complement with Loss of Hippocampal Mossy Fiber Synapses Induced by Trimethyltin.
abstract: Complement-associated factors are implicated in pathogen presentation, neurodegeneration, and microglia resolution of tissue injury. To characterize complement activation with microglial clearance of degenerating mossy fiber boutons, hippocampal dentate granule neurons were ablated in CD-1 mice with trimethyltin (TMT; 2.2 mg/kg, i.p.). Neuronal apoptosis was accompanied by amoeboid microglia and elevations in tumor necrosis factor [Tnfa], interleukin 1β [Il1b], and Il6 mRNA and C1q protein. Inos mRNA levels were unaltered. Silver degeneration and synaptophysin staining indicated loss of synaptic innervation to CA3 pyramidal neurons. Reactive microglia with thickened bushy morphology showed co-localization of synaptophysin+ fragments. The initial response at 2 days post-TMT included transient elevations in Tnfa, Il1b, Il6, and Inos mRNA levels. A concurrent increase at 2 days was observed in arginase-1 [Arg1], Il10, transforming growth factor β1 [Tgfb1], and chitinase 3 like-3 [Ym1] mRNA levels. At 2 days, C1q protein was evident in the CA3 with elevated C1qa, C1qb, C3, Cr3a, and Cr3b mRNA levels. mRNA levels remained elevated at 5 days, returning to control by 14 days, corresponding to silver degeneration. mRNA levels for pentraxin3 (Ptx3) were elevated on day 2 and Ptx1 was not altered. Our data suggest an association between microglia reactivity, the induction of anti-inflammatory genes concurrent with pro-inflammatory genes and the expression of complement-associated factors with the degeneration of synapses following apoptotic neuronal loss.
authors.affiliation: Neurotoxicology Group, National Toxicology Program Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, P.O. Box 12233, Mail Drop E1-07, Research Triangle Park, NC, 27709, USA.|National Center for Environmental Assessment, U.S. Environmental Protection Agency, Washington, DC, 20460, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Kraft
authors.affiliation: Neurotoxicology Group, National Toxicology Program Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, P.O. Box 12233, Mail Drop E1-07, Research Triangle Park, NC, 27709, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: McPherson
authors.affiliation: Neurotoxicology Group, National Toxicology Program Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, P.O. Box 12233, Mail Drop E1-07, Research Triangle Park, NC, 27709, USA. harry@niehs.nih.gov.
authors.forename: G Jean
authors.initials: GJ
authors.lastname: Harry
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001119:Arginase / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D003165:Complement System Proteins / Q000378:metabolism*; D018891:Dentate Gyrus / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D037102:Lectins / Q000378:metabolism; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D019599:Mossy Fibers, Hippocampal / Q000378:metabolism* / Q000473:pathology; D009410:Nerve Degeneration / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051761:Paired Box Transcription Factors / Q000378:metabolism; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D016708:Synaptophysin / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014298:Trimethyltin Compounds / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism; D000099153:Pentraxins
chemical_list: D001119:Arginase; D002097:C-Reactive Protein; D003165:Complement System Proteins; D018836:Inflammation Mediators; D016753:Interleukin-10; D053583:Interleukin-1beta; D015850:Interleukin-6; D037102:Lectins; D009419:Nerve Tissue Proteins; D052247:Nitric Oxide Synthase Type II; D051761:Paired Box Transcription Factors; D016708:Synaptophysin; D016212:Transforming Growth Factor beta; D014298:Trimethyltin Compounds; D014409:Tumor Necrosis Factor-alpha; D001619:beta-N-Acetylhexosaminidases; D000099153:Pentraxins; C101485:homeobox protein PITX1; C046488:trimethyltin; C496317:Nos2 protein, mouse; C429541:Chil3 protein, mouse; C544448:Arg1 protein, mouse
keywords: C1q; Interleukin 1; M1/M2 polarization; Microglia; Synapse stripping; Tumor necrosis factor