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The Journal of Neuroscience, April 22, 2009, 29(16):5051-5061; doi:10.1523/JNEUROSCI.0324-09.2009

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Neurobiology of Disease
Rett Syndrome Astrocytes Are Abnormal and Spread MeCP2 Deficiency through Gap Junctions

Izumi Maezawa,^1,2 Susan Swanberg,³ Danielle Harvey,⁴ Janine M. LaSalle,³ and Lee-Way Jin^1,2

¹M.I.N.D. (Medical Investigation of Neurodevelopmental Disorders) Institute and ²Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, Sacramento, California 95817, and ³Department of Medical Microbiology and Immunology and ⁴Division of Biostatistics, Department of Public Health Sciences, University of California Davis School of Medicine, Davis, California 95618

Correspondence should be addressed to Dr. Lee-Way Jin, M.I.N.D. (Medical Investigation of Neurodevelopmental Disorders) Institute and Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, Sacramento, CA 95817. Email: lee-way.jin{at}ucdmc.ucdavis.edu

MECP2, an X-linked gene encoding the epigenetic factor methyl-CpG-binding protein-2, is mutated in Rett syndrome (RTT) and aberrantly expressed in autism. Most children affected by RTT are heterozygous Mecp2^–/+ females whose brain function is impaired postnatally due to MeCP2 deficiency. While prior functional investigations of MeCP2 have focused exclusively on neurons and have concluded the absence of MeCP2 in astrocytes, here we report that astrocytes express MeCP2, and MeCP2 deficiency in astrocytes causes significant abnormalities in BDNF regulation, cytokine production, and neuronal dendritic induction, effects that may contribute to abnormal neurodevelopment. In addition, we show that the MeCP2 deficiency state can progressively spread at least in part via gap junction communications between mosaic Mecp2^–/+ astrocytes in a novel non-cell-autonomous mechanism. This mechanism may lead to the pronounced loss of MeCP2 observed selectively in astrocytes in mouse Mecp2^–/+ brain, which is coincident with phenotypic regression characteristic of RTT. Our results suggest that astrocytes are viable therapeutic targets for RTT and perhaps regressive forms of autism.

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Received Jan. 20, 2009; revised Feb. 23, 2009; accepted March 7, 2009.

Correspondence should be addressed to Dr. Lee-Way Jin, M.I.N.D. (Medical Investigation of Neurodevelopmental Disorders) Institute and Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, Sacramento, CA 95817. Email: lee-way.jin{at}ucdmc.ucdavis.edu

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