title: Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor.
abstract: Microglia are the resident macrophages of the CNS, and their functions have been extensively studied in various brain pathologies. The physiological roles of microglia in brain plasticity and function, however, remain unclear. To address this question, we generated CX3CR1(CreER) mice expressing tamoxifen-inducible Cre recombinase that allow for specific manipulation of gene function in microglia. Using CX3CR1(CreER) to drive diphtheria toxin receptor expression in microglia, we found that microglia could be specifically depleted from the brain upon diphtheria toxin administration. Mice depleted of microglia showed deficits in multiple learning tasks and a significant reduction in motor-learning-dependent synapse formation. Furthermore, Cre-dependent removal of brain-derived neurotrophic factor (BDNF) from microglia largely recapitulated the effects of microglia depletion. Microglial BDNF increases neuronal tropomyosin-related kinase receptor B phosphorylation, a key mediator of synaptic plasticity. Together, our findings reveal that microglia serve important physiological functions in learning and memory by promoting learning-related synapse formation through BDNF signaling.
authors.affiliation: Molecular Neurobiology Program, The Kimmel Center for Biology and Medicine at the Skirball Institute, Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Parkhurst
authors.affiliation: Department of Anesthesiology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Ipe
authors.initials: I
authors.lastname: Ninan
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Savas
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.affiliation: Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine at the Skirball Institute, Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Lafaille
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Hempstead
authors.affiliation: Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine at the Skirball Institute, Department of Pathology, New York University School of Medicine, New York, NY 10016, USA; Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Dan R
authors.initials: DR
authors.lastname: Littman
authors.affiliation: Molecular Neurobiology Program, The Kimmel Center for Biology and Medicine at the Skirball Institute, Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY 10016, USA. Electronic address: wenbiao.gan@nyumc.org.
authors.forename: Wen-Biao
authors.initials: WB
authors.lastname: Gan
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D000073883:CX3C Chemokine Receptor 1; D015870:Gene Expression; D007858:Learning / Q000502:physiology*; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000502:physiology*; D009473:Neuronal Plasticity; D011494:Protein Kinases / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D019707:Receptors, Chemokine; D011494:Protein Kinases