Loss of activity-induced phosphorylation of MeCP2 enhances synaptogenesis, LTP and spatial memory
Open Access
- 17 July 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Neuroscience
- Vol. 14 (8), 1001-1008
- https://doi.org/10.1038/nn.2866
Abstract
The authors generated a knock-in mouse line in which the MeCP2 protein cannot be phosphorylated by neuronal activity, and found that the mice exhibit superior hippocampus-dependent memory performance and enhanced synaptic plasticity by upregulating MeCP2 target genes, including BDNF, and have higher levels of excitatory synaptogenesis. DNA methylation–dependent epigenetic mechanisms underlie the development and function of the mammalian brain. MeCP2 is highly expressed in neurons and functions as a molecular linker between DNA methylation, chromatin remodeling and transcription regulation. Previous in vitro studies have shown that neuronal activity–induced phosphorylation (NAIP) of methyl CpG–binding protein 2 (MeCP2) precedes its release from the Bdnf promoter and the ensuing Bdnf transcription. However, the in vivo function of this phosphorylation event remains elusive. We generated knock-in mice that lack NAIP of MeCP2 and found that they performed better in hippocampus-dependent memory tests, presented enhanced long-term potentiation at two synapses in the hippocampus and showed increased excitatory synaptogenesis. At the molecular level, the phospho-mutant MeCP2 protein bound more tightly to several MeCP2 target gene promoters and altered the expression of these genes. Our results suggest that NAIP of MeCP2 is required for modulating dynamic functions of the adult mouse brain.Keywords
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