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Loss of activity-induced phosphorylation of MeCP2 enhances synaptogenesis, LTP and spatial memory

Nature Neuroscience volume 14, pages 1001–1008 (2011)Cite this article

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Abstract

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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Figure 1: Phosphorylation at serine 421 induced by depolarization, HFS and behavioral training.
Figure 2: Loss of NAIP at S421 in the Mecp2S421A;S424A/y mice.
Figure 3: Enhanced contextual fear memory in the Mecp2S421A;S424A/y mice.
Figure 4: Enhanced spatial memory in the Mecp2S421A;S424A/y mice.
Figure 5: Enhanced Schaffer collateral–CA1 LTP in Mecp2S421A;S424A/y mice.
Figure 6: Enhanced mossy fiber–CA3 LTP in Mecp2S421A;S424A/y mice.
Figure 7: Increased excitatory synaptogenesis in Mecp2S421A;S424A/y mice.
Figure 8: Altered expression of MeCP2 target genes in the hippocampus of the Mecp2S421A;S424A/y mice and increased promoter binding by the Flag-tagged mutant MeCP2.

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Acknowledgements

We thank A. Messing, J. Svaren and J. Yin for critically reading the manuscript, S. Marwaha for assistance with mouse work, and M. Andrzejewski for assistance with statistical analysis. H.L. was supported by a pre-doctoral fellowship from the Stem Cell and Regenerative Medicine Center at the University of Wisconsin, Madison. E.C.W. was supported by a predoctoral training grant (5T32GM07133) and a graduate student fellowship from the Friends of the Waisman Center. Q.C. was supported by a Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression. This work was partially supported by grants from the National Institute of Child Health and Human Development (R01 HD064743 and R21 HD066560 to Q.C., and P30 HD03352 to the Waisman Center).

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Authors and Affiliations

  1. Genetics Training Program, University of Wisconsin-Madison, Madison, Wisconsin, USA

    Hongda Li, Emily Cunningham Williams & Qiang Chang

  2. Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA

    Hongda Li, Xiaofen Zhong, Kevin Fongching Chau, Emily Cunningham Williams & Qiang Chang

  3. Department of Genetics and Neurology, University of Wisconsin-Madison, Madison, Wisconsin, USA

    Qiang Chang

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  1. Hongda Li
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Contributions

Q.C. directed the studies. H.L., X.Z. and Q.C. conceived and designed the experiments. H.L. performed the western blot, mouse behavioral tests, ChIP experiments, gene expression studies, imaging and image analysis. K.F.C. performed mouse behavioral tests. X.Z. performed all of the electrophysiology experiments, neuronal culture and hippocampal slice experiments, and immunostaining. E.C.W. performed immunostaining. The paper was written by Q.C., H.L. and X.Z. and commented on by all authors.

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Correspondence to Qiang Chang.

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Li, H., Zhong, X., Chau, K. et al. Loss of activity-induced phosphorylation of MeCP2 enhances synaptogenesis, LTP and spatial memory. Nat Neurosci 14, 1001–1008 (2011). https://doi.org/10.1038/nn.2866

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