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Association Between Microglia, Inflammatory Factors, and Complement with Loss of Hippocampal Mossy Fiber Synapses Induced by Trimethyltin

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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.

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Acknowledgments

This research was supported by the Division of Intramural Research and the Division of National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services #1Z01ES101623 and ES021164. The authors graciously acknowledge the generous gift of C1q antibody from Dr. Andrea Tenner at the University of California-Irvine, and FD NeuroTechnologies for the CuAg staining. The views expressed in this article are those of the authors and they do not necessarily represent the views or policies of the US EPA.

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    Present address: National Center for Environmental Assessment, U.S. Environmental Protection Agency, Washington, DC, 20460, USA

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  1. 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

    Andrew D. Kraft, Christopher A. McPherson & G. Jean Harry

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Kraft, A.D., McPherson, C.A. & Harry, G.J. Association Between Microglia, Inflammatory Factors, and Complement with Loss of Hippocampal Mossy Fiber Synapses Induced by Trimethyltin. Neurotox Res 30, 53–66 (2016). https://doi.org/10.1007/s12640-016-9606-8

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