Brain. 2006 Feb 8; [Epub ahead of print]
Mecp2 deficiency is associated with learning and cognitive deficits and altered gene activity in the hippocampal region of mice
Pelka GJ, Watson CM, Radziewic T, Hayward M, Lahooti H, Christodoulou J, Tam PP.
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.
Lay Summary
Until recently, three independent groups had generated MeCP2-deficient mice models of Rett syndrome, all of which and are widely used in Rett research. In this report, the authors describe a fourth mouse model of Rett syndrome, featuring a mouse completely devoid of MeCP2 activity. As anticipated, this mouse develops Rett-like symptoms found in the other mouse models, including alterations in growth, learning deficits, movement disorder, and altered anxiety. Interestingly, the authors examined the contribution of the Y chromosome to the disease progression, but found no influence. In summary, the authors discuss and characterize a new model mouse for use in Rett syndrome research, thus providing a valuable new resource for the research community.