title: Morphological and functional reversal of phenotypes in a mouse model of Rett syndrome.
abstract: Rett syndrome is a neurological disorder caused by mutation of the X-linked MECP2 gene. Mice lacking functional Mecp2 display a spectrum of Rett syndrome-like signs, including disturbances in motor function and abnormal patterns of breathing, accompanied by structural defects in central motor areas and the brainstem. Although routinely classified as a neurodevelopmental disorder, many aspects of the mouse phenotype can be effectively reversed by activation of a quiescent Mecp2 gene in adults. This suggests that absence of Mecp2 during brain development does not irreversibly compromise brain function. It is conceivable, however, that deep-seated neurological defects persist in mice rescued by late activation of Mecp2. To test this possibility, we have quantitatively analysed structural and functional plasticity of the rescued adult male mouse brain. Activation of Mecp2 in ∼70% of neurons reversed many morphological defects in the motor cortex, including neuronal size and dendritic complexity. Restoration of Mecp2 expression was also accompanied by a significant improvement in respiratory and sensory-motor functions, including breathing pattern, grip strength, balance beam and rotarod performance. Our findings sustain the view that MeCP2 does not play a pivotal role in brain development, but may instead be required to maintain full neurological function once development is complete.
authors.affiliation: School of Medical Sciences, University of Aberdeen, Forresterhill, Aberdeen, AB25 2ZD, UK.
authors.forename: Lianne
authors.initials: L
authors.lastname: Robinson
authors.forename: Jacky
authors.initials: J
authors.lastname: Guy
authors.forename: Leanne
authors.initials: L
authors.lastname: McKay
authors.forename: Emma
authors.initials: E
authors.lastname: Brockett
authors.forename: Rosemary C
authors.initials: RC
authors.lastname: Spike
authors.forename: Jim
authors.initials: J
authors.lastname: Selfridge
authors.forename: Dina
authors.initials: D
authors.lastname: De Sousa
authors.forename: Cara
authors.initials: C
authors.lastname: Merusi
authors.forename: Gernot
authors.initials: G
authors.lastname: Riedel
authors.forename: Adrian
authors.initials: A
authors.lastname: Bird
authors.forename: Stuart R
authors.initials: SR
authors.lastname: Cobb
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D020868:Gene Silencing; D018737:Hand Strength / Q000502:physiology; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D015518:Rett Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D045442:Rotarod Performance Test
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2