title: Microglial CX3CR1 promotes adult neurogenesis by inhibiting Sirt 1/p65 signaling independent of CX3CL1.
abstract: Homo and heterozygote cx3cr1 mutant mice, which harbor a green fluorescent protein (EGFP) in their cx3cr1 loci, represent a widely used animal model to study microglia and peripheral myeloid cells. Here we report that microglia in the dentate gyrus (DG) of cx3cr1 (-/-) mice displayed elevated microglial sirtuin 1 (SIRT1) expression levels and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) p65 activation, despite unaltered morphology when compared to cx3cr1 (+/-) or cx3cr1 (+/+) controls. This phenotype was restricted to the DG and accompanied by reduced adult neurogenesis in cx3cr1 (-/-) mice. Remarkably, adult neurogenesis was not affected by the lack of the CX3CR1-ligand, fractalkine (CX3CL1). Mechanistically, pharmacological activation of SIRT1 improved adult neurogenesis in the DG together with an enhanced performance of cx3cr1 (-/-) mice in a hippocampus-dependent learning and memory task. The reverse condition was induced when SIRT1 was inhibited in cx3cr1 (-/-) mice, causing reduced adult neurogenesis and lowered hippocampal cognitive abilities. In conclusion, our data indicate that deletion of CX3CR1 from microglia under resting conditions modifies brain areas with elevated cellular turnover independent of CX3CL1.
authors.affiliation: Institute of Neuropathology, University of Freiburg, Breisacher Str. 64, D-79106, Freiburg, Germany.|Present Address: Laboratory of Experimental Stroke Research, Institute for Stroke and Dementia Research (ISD), University of Munich Medical Center, 81377, Munich, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Sellner
authors.affiliation: Institute of Neuropathology, University of Freiburg, Breisacher Str. 64, D-79106, Freiburg, Germany.|Present Address: Department of Neuroscience, Max Delbrück Center for Molecular Medicine (MDC), Berlin-Buch, Robert-Rössle-Str. 10, 13092, Berlin, Germany.|Present Address: Cluster of Excellence NeuroCure, Neuroscience Research Center, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Paricio-Montesinos
authors.affiliation: Institute of Neuropathology, University of Freiburg, Breisacher Str. 64, D-79106, Freiburg, Germany.
authors.forename: Alena
authors.initials: A
authors.lastname: Spieß
authors.affiliation: Department of Psychiatry and Psychotherapy, Freiburg, Germany.|Present Address: Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Ferdinand-Sauerbruch-Str., 17475, Greifswald, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Masuch
authors.affiliation: Institute of Neuropathology, University of Freiburg, Breisacher Str. 64, D-79106, Freiburg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Erny
authors.affiliation: Department of Radiology, Medical Physics, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Harsan
authors.affiliation: Department of Radiology, Medical Physics, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Dominik V
authors.initials: DV
authors.lastname: Elverfeldt
authors.affiliation: Institute of Neuropathology, University of Freiburg, Breisacher Str. 64, D-79106, Freiburg, Germany.
authors.forename: Marius
authors.initials: M
authors.lastname: Schwabenland
authors.affiliation: Department of Psychiatry and Psychotherapy, Freiburg, Germany.|Department of Neuroscience, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Knut
authors.initials: K
authors.lastname: Biber
authors.affiliation: Institute of Neuropathology, University of Freiburg, Breisacher Str. 64, D-79106, Freiburg, Germany.
authors.forename: Ori
authors.initials: O
authors.lastname: Staszewski
authors.affiliation: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Sergio
authors.initials: S
authors.lastname: Lira
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Steffen
authors.initials: S
authors.lastname: Jung
authors.affiliation: Institute of Neuropathology, University of Freiburg, Breisacher Str. 64, D-79106, Freiburg, Germany.|BIOSS Center for Biological Signaling Studies, University of Freiburg, Freiburg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.affiliation: Institute of Neuropathology, University of Freiburg, Breisacher Str. 64, D-79106, Freiburg, Germany. thomas.blank@uniklinik-freiburg.de.
authors.forename: Thomas
authors.identifier: 0000-0002-3969-405X
authors.initials: T
authors.lastname: Blank
mesh_terms: D053687:Adult Stem Cells / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D054428:Chemokine CX3CL1 / Q000235:genetics / Q000378:metabolism; D000089622:Doublecortin Domain Proteins; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000187:drug effects / Q000502:physiology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism*; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism; D023062:Receptors, Interleukin-8A / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D055153:Stem Cell Niche / Q000187:drug effects / Q000502:physiology; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; D000089622:Doublecortin Domain Proteins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D023062:Receptors, Interleukin-8A; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Adult neurogenesis; Microglia; Morphometry; NF-kB p65 acetylation; Sirtuin 1; Water maze