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Brain Advance Access published online on February 8, 2006
Brain, 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
Received July 18, 2005
Revised September 27, 2005
Accepted January 5, 2006

Article

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

Gregory J. Pelka 1, Catherine M. Watson 2, Tania Radziewic 2, Melinda Hayward 2, Hooshang Lahooti 3, John Christodoulou 4, and Patrick P. L. Tam 2 *

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

* To whom correspondence should be addressed.
Patrick P. L. Tam, E-mail: ptam{at}cmri.usyd.edu.au


  Abstract

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.

Keywords: Rett syndrome; methyl CpG-binding protein 2; gene expression; behaviour; hippocampal formation.
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