lunes, 12 de abril de 2010

Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons


Nature Neuroscience | Article

Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons

Jian Feng,Yu Zhou,Susan L Campbell,Thuc Le,En Li,J David Sweatt,Alcino J Silva& Guoping Fan

Affiliations Contributions Corresponding author Journal name: Nature Neuroscience
Volume: 13,
Pages: 423–430
Year published: (2010)
DOI: doi:10.1038/nn.2514
Received 14 December 2009 Accepted 15 February 2010 Published online 14 March 2010


Abstract

Dnmt1 and Dnmt3a are important DNA methyltransferases that are expressed in postmitotic neurons, but their function in the CNS is unclear. We generated conditional mutant mice that lack Dnmt1, Dnmt3a or both exclusively in forebrain excitatory neurons and found that only double knockout (DKO) mice showed abnormal long-term plasticity in the hippocampal CA1 region together with deficits in learning and memory. Although we found no neuronal loss, hippocampal neurons in DKO mice were smaller than in the wild type; furthermore, DKO neurons showed deregulated expression of genes, including the class I MHC genes and Stat1, that are known to contribute to synaptic plasticity. In addition, we observed a significant decrease in DNA methylation in DKO neurons. We conclude that Dnmt1 and Dnmt3a are required for synaptic plasticity, learning and memory through their overlapping roles in maintaining DNA methylation and modulating neuronal gene expression in adult CNS neurons.

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http://www.nature.com/neuro/journal/v13/n4/full/nn.2514.html

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