A role for glia in the progression of Rett’s syndrome

• Published in: Nature (London) 2011-07, Vol.475 (7357), p.497-500
• Main Authors: Lioy, Daniel T., Garg, Saurabh K., Monaghan, Caitlin E., Raber, Jacob, Foust, Kevin D., Kaspar, Brian K., Hirrlinger, Petra G., Kirchhoff, Frank, Bissonnette, John M., Ballas, Nurit, Mandel, Gail
• Format: Article
• Language: English
• Subjects: 631/208/199; 631/378/1689/1373; 631/378/2571/219; Abnormalities; Animals; Anxiety; Anxiety - metabolism; Astrocytes - metabolism; Behavior; Behavior, Animal; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Development and progression; Disease Progression; Evacuations & rescues; Female; Gene Expression Regulation; Genetic aspects; Humanities and Social Sciences; letter; Male; Medical sciences; Methyl-CpG-Binding Protein 2 - deficiency; Methyl-CpG-Binding Protein 2 - genetics; Methyl-CpG-Binding Protein 2 - metabolism; Mice; Mice, Inbred C57BL; Motor Activity; multidisciplinary; Neuroglia; Neuroglia - metabolism; Neuroglia - pathology; Neurology; Neurons - metabolism; Rett syndrome; Rett Syndrome - genetics; Rett Syndrome - metabolism; Rett Syndrome - physiopathology; Rodents; Science; Science (multidisciplinary); Studies; Vesicular Glutamate Transport Protein 1 - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature10214

Astrocytes targeted in Rett's syndrome Rett's syndrome, a disorder caused by loss of function of methyl CpG-binding protein 2 (MeCP2), is associated with various neurological symptoms on the autism spectrum. Although impaired neurons are the underlying cause of nervous system failure in Rett's syndrome, experiments in a mouse model show that the genetic correction of MeCP2 expression in glial cells — principally in astrocytes — can reverse three hallmark behaviour abnormalities of the neurological disorder. Neuronal morphology and neurotransmitter markers are also rescued, suggesting an interactive mechanism between glial and neuronal cells in Rett's syndrome initiation and progression. 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) 1 . Although MeCP2 is expressed in most tissues 2 , loss of MeCP2 expression results primarily in neurological symptoms 1 , 3 , 4 . Earlier studies suggested the idea that RTT is due exclusively to loss of MeCP2 function in neurons 2 , 4 , 5 , 6 , 7 , 8 , 9 , 10 . 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 11 , 12 , 13 . 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.