title: Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression.
abstract: Microglia, the resident CNS macrophages, have been implicated in the pathogenesis of Rett Syndrome (RTT), an X-linked neurodevelopmental disorder. However, the mechanism by which microglia contribute to the disorder is unclear and recent data suggest that microglia do not play a causative role. Here, we use the retinogeniculate system to determine if and how microglia contribute to pathogenesis in a RTT mouse model, the Mecp2 null mouse (Mecp2(tm1.1Bird/y)). We demonstrate that microglia contribute to pathogenesis by excessively engulfing, thereby eliminating, presynaptic inputs at end stages of disease (≥P56 Mecp2 null mice) concomitant with synapse loss. Furthermore, loss or gain of Mecp2 expression specifically in microglia (Cx3cr1(CreER);Mecp2(fl/y)or Cx3cr1(Cr)(eER); Mecp2(LSL/y)) had little effect on excessive engulfment, synapse loss, or phenotypic abnormalities. Taken together, our data suggest that microglia contribute to end stages of disease by dismantling neural circuits rendered vulnerable by loss of Mecp2 in other CNS cell types.
authors.affiliation: FM Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, United States.|Department of Neurobiology, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Dorothy P
authors.identifier: 0000-0003-2201-6276
authors.initials: DP
authors.lastname: Schafer
authors.affiliation: FM Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, United States.|Department of Neurobiology, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Heller
authors.affiliation: FM Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, United States.|Department of Neurobiology, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Georgia
authors.initials: G
authors.lastname: Gunner
authors.affiliation: FM Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, United States.
authors.forename: Molly
authors.initials: M
authors.lastname: Heller
authors.affiliation: FM Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Gordon
authors.affiliation: FM Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, United States.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hammond
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yochai
authors.initials: Y
authors.lastname: Wolf
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Steffen
authors.initials: S
authors.lastname: Jung
authors.affiliation: FM Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, United States.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, United States.
authors.forename: Beth
authors.initials: B
authors.lastname: Stevens
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004705:Endocytosis; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D015518:Rett Syndrome / Q000473:pathology* / Q000503:physiopathology*; D013569:Synapses / Q000502:physiology
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2
keywords: Mecp2; Rett Syndrome; engulfment; microglia; mouse; neuroscience; synapse