title: A role for glia in the progression of Rett's syndrome.
abstract: Rett's syndrome (RTT) is an X-chromosome-linked autism spectrum disorder caused by loss of function of the transcription factor methyl-CpG-binding protein 2 (MeCP2). Although MeCP2 is expressed in most tissues, loss of MeCP2 expression results primarily in neurological symptoms. Earlier studies suggested the idea that RTT is due exclusively to loss of MeCP2 function in neurons. Although defective neurons clearly underlie the aberrant behaviours, we and others showed recently that the loss of MECP2 from glia negatively influences neurons in a non-cell-autonomous fashion. Here we show that in globally MeCP2-deficient mice, re-expression of Mecp2 preferentially in astrocytes significantly improved locomotion and anxiety levels, restored respiratory abnormalities to a normal pattern, and greatly prolonged lifespan compared to globally null mice. Furthermore, restoration of MeCP2 in the mutant astrocytes exerted a non-cell-autonomous positive effect on mutant neurons in vivo, restoring normal dendritic morphology and increasing levels of the excitatory glutamate transporter VGLUT1. Our study shows that glia, like neurons, are integral components of the neuropathology of RTT, and supports the targeting of glia as a strategy for improving the associated symptoms.
authors.affiliation: Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239, USA.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Lioy
authors.forename: Saurabh K
authors.initials: SK
authors.lastname: Garg
authors.forename: Caitlin E
authors.initials: CE
authors.lastname: Monaghan
authors.forename: Jacob
authors.initials: J
authors.lastname: Raber
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Foust
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kaspar
authors.forename: Petra G
authors.initials: PG
authors.lastname: Hirrlinger
authors.forename: Frank
authors.initials: F
authors.lastname: Kirchhoff
authors.forename: John M
authors.initials: JM
authors.lastname: Bissonnette
authors.forename: Nurit
authors.initials: N
authors.lastname: Ballas
authors.forename: Gail
authors.initials: G
authors.lastname: Mandel
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism; D001522:Behavior, Animal; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D015518:Rett Syndrome / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D050598:Vesicular Glutamate Transport Protein 1