title: CX3CR1 ablation ameliorates motor and respiratory dysfunctions and improves survival of a Rett syndrome mouse model.
abstract: Rett syndrome (RTT) is a neurodevelopmental disorder caused by loss-of-function mutations in the gene encoding MeCP2, an epigenetic modulator that binds the methyl CpG dinucleotide in target genes to regulate transcription. Previously we and others reported a role of microglia in the pathophysiology of RTT. Because microglia in the Mecp2 knockout (Mecp2KO) mouse model of RTT over-produce neurotoxic mediators glutamate and reactive oxygen species, we hypothesize that blocking neuron-microglia interaction by ablation of CX3CR1, a chemokine receptor expressed in microglia/myeloid cells mediating such interaction by pairing with its neuronal ligand CX3CL1, would ameliorate the RTT-like phenotype in Mecp2KO mice. Here we report that CX3CR1 ablation prolonged the lifespan of Mecp2KO mice from a median survival of 54.5-74days, and significantly improved the body weight gain, symptomatic scores, major respiratory parameters, and motor coordination and performance. CX3CR1 ablation rectified previously identified histological abnormalities in the Mecp2KO brain such as neuronal soma size in hippocampal CA2, and the number, soma size, and process complexity of microglia. Moreover, CX3CR1 ablation enhanced the neurotrophic action of microglia in Mecp2KO mice by producing higher amount of insulin-like growth factor 1. Our data support a role of myeloid cells/microglia in RTT and suggest a novel therapeutic approach for RTT by targeting CX3CR1 with specific antagonists or genetic downregulation.
authors.affiliation: Department of Pathology and Laboratory Medicine, 2805 50th Street, UC Davis Medical Center, Sacramento, CA 95817, United States.
authors.forename: Makoto
authors.initials: M
authors.lastname: Horiuchi
authors.affiliation: Department of Pathology and Laboratory Medicine, 2805 50th Street, UC Davis Medical Center, Sacramento, CA 95817, United States.
authors.forename: Lucas
authors.initials: L
authors.lastname: Smith
authors.affiliation: Department of Pathology and Laboratory Medicine, 2805 50th Street, UC Davis Medical Center, Sacramento, CA 95817, United States; M.I.N.D. (Medical Investigation of Neurodevelopmental Disorders) Institute, 2805 50th Street, UC Davis Medical Center, Sacramento, CA 95817, United States.
authors.forename: Izumi
authors.initials: I
authors.lastname: Maezawa
authors.affiliation: Department of Pathology and Laboratory Medicine, 2805 50th Street, UC Davis Medical Center, Sacramento, CA 95817, United States; M.I.N.D. (Medical Investigation of Neurodevelopmental Disorders) Institute, 2805 50th Street, UC Davis Medical Center, Sacramento, CA 95817, United States. Electronic address: lwjin@ucdavis.edu.
authors.forename: Lee-Way
authors.initials: LW
authors.lastname: Jin
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D000073883:CX3C Chemokine Receptor 1 / Q000235:genetics*; D004195:Disease Models, Animal; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015518:Rett Syndrome / Q000235:genetics / Q000401:mortality*
chemical_list: D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D017382:Reactive Oxygen Species
keywords: CX(3)CR1; MeCP2; Microglia; Rett syndrome