Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor

Christopher N Parkhurst; Guang Yang; Ipe Ninan; Jeffrey N Savas; John R Yates 3rd; Juan J Lafaille; Barbara L Hempstead; Dan R Littman; Wen-Biao Gan

doi:10.1016/j.cell.2013.11.030

Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor

Cell. 2013 Dec 19;155(7):1596-609. doi: 10.1016/j.cell.2013.11.030.

Authors

Christopher N Parkhurst¹, Guang Yang², Ipe Ninan³, Jeffrey N Savas⁴, John R Yates 3rd⁴, Juan J Lafaille⁵, Barbara L Hempstead⁶, Dan R Littman⁷, Wen-Biao Gan⁸

Affiliations

¹ 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.
² Department of Anesthesiology, New York University School of Medicine, New York, NY 10016, USA.
³ Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA.
⁴ Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁵ 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.
⁶ Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
⁷ 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.
⁸ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain-Derived Neurotrophic Factor / metabolism*
CX3C Chemokine Receptor 1
Gene Expression
Learning / physiology*
Mice
Microglia / cytology
Microglia / physiology*
Neuronal Plasticity
Protein Kinases / metabolism
Receptors, Chemokine / genetics
Receptors, Chemokine / metabolism
Signal Transduction
Synapses*

Substances

Brain-Derived Neurotrophic Factor
CX3C Chemokine Receptor 1
Cx3cr1 protein, mouse
Receptors, Chemokine
Protein Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding