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Brain Advance Access originally published online on February 8, 2006
Brain 2006 129(4):887-898; doi:10.1093/brain/awl022
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© The Author (2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Mecp2 deficiency is associated with learning and cognitive deficits and altered gene activity in the hippocampal region of mice

Gregory J. Pelka1,2,3, Catherine M. Watson1, Tania Radziewic1, Melinda Hayward1, Hooshang Lahooti3, John Christodoulou2,3 and Patrick P. L. Tam1

1 Embryology Unit, Children's Medical Research Institute, 2 Discipline of Paediatrics and Child Health, University of Sydney and 3 Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, NSW, Australia

Correspondence to: Patrick P. L. Tam, Embryology Unit, Children's Medical Research Institute, Locked Bag 23, Wentworthville, NSW 2145, Australia E-mail: ptam{at}cmri.usyd.edu.au

Rett syndrome (RTT) is a debilitating neurological condition associated with mutations in the X-linked MECP2 gene, where apparently normal development is seen prior to the onset of cognitive and motor deterioration at 6–18 months of life. A targeted deletion of the methyl-CpG-binding domain (MBD) coding region and disruption of mRNA splicing was introduced in the mouse, resulting in a complete loss of Mecp2 transcripts and protein. Postnatal comparison of XO and XY mutant Mecp2 allele-containing null mice revealed similar effects on mouse growth and viability, suggesting that phenotypic manifestations are not modulated by the Y-chromosome. Further assessment of Mecp2-null XY mice highlighted cerebellar and hippocampal/amygdala-based learning deficits in addition to reduced motor dexterity and decreased anxiety levels. Brain tissues containing the hippocampal formation of XY Mecp2-null mice also displayed significant changes in genetic activity, which are related to the severity of the mutant phenotype.

Key Words: Rett syndrome; methyl CpG-binding protein 2; gene expression; behaviour; hippocampal formation

Abbreviations: ES = embryonic stem; MBD = methyl-CpG-binding domain; MeCP2 = methyl-CpG-binding protein 2; QRT–PCR = quantitative real time reverse transcription–polymerase chain reaction; RTT = Rett syndrome; TRD = transcriptional repression domain

Received July 18, 2005. Revised September 27, 2005. Accepted January 5, 2006.


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