期刊
NATURE NEUROSCIENCE
卷 14, 期 8, 页码 1001-U89出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.2866
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资金
- Stem Cell and Regenerative Medicine Center at the University of Wisconsin, Madison
- Friends of the Waisman Center [5T32GM07133]
- National Alliance for Research on Schizophrenia and Depression
- National Institute of Child Health and Human Development [R01 HD064743, R21 HD066560, P30 HD03352]
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.
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