title: Microglial CR3 activation triggers long-term synaptic depression in the hippocampus via NADPH oxidase.
abstract: Complement receptor 3 (CR3) activation in microglia is involved in neuroinflammation-related brain disorders and pruning of neuronal synapses. Hypoxia, often observed together with neuroinflammation in brain trauma, stroke, and neurodegenerative diseases, is thought to exacerbate inflammatory responses and synergistically enhance brain damage. Here we show that when hypoxia and an inflammatory stimulus (lipopolysaccharide [LPS]) are combined, they act synergistically to trigger long-term synaptic depression (LTD) that requires microglial CR3, activation of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), and GluA2-mediated A-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization. Microglial CR3-triggered LTD is independent of N-methyl-D-aspartate receptors (NMDARs), metabotropic glutamate receptors (mGluRs), or patterned synaptic activity. This type of LTD may contribute to memory impairments and synaptic disruptions in neuroinflammation-related brain disorders.
authors.affiliation: Brain Research Centre, Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
authors.forename: Jingfei
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Brain Research Centre, Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
authors.forename: Aqsa
authors.initials: A
authors.lastname: Malik
authors.affiliation: Brain Research Centre, Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
authors.forename: Hyun B
authors.initials: HB
authors.lastname: Choi
authors.affiliation: Brain Research Centre, Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
authors.forename: Rebecca W Y
authors.initials: RW
authors.lastname: Ko
authors.affiliation: Brain Research Centre, Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
authors.forename: Lasse
authors.initials: L
authors.lastname: Dissing-Olesen
authors.affiliation: Brain Research Centre, Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada. Electronic address: bmacvicar@brain.ubc.ca.
authors.forename: Brian A
authors.initials: BA
authors.lastname: MacVicar
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D039481:CD11b Antigen / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000502:physiology*; D000860:Hypoxia / Q000503:physiopathology; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000235:genetics; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism*; D010100:Oxygen / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000098:Acetophenones; D039481:CD11b Antigen; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D016177:Macrophage-1 Antigen; C056165:acetovanillone; D007770:L-Lactate Dehydrogenase; D019255:NADPH Oxidases; D010100:Oxygen