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REST-dependent epigenetic remodeling promotes the developmental switch in synaptic NMDA receptors

Nature Neuroscience volume 15, pages 1382–1390 (2012)Cite this article

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Abstract

NMDA receptors (NMDARs) are critical to synaptogenesis, neural circuitry and higher cognitive functions. A hallmark feature of NMDARs is an early postnatal developmental switch from those containing primarily GluN2B to primarily GluN2A subunits. Although the switch in phenotype has been an area of intense interest for two decades, the mechanisms that trigger it and the link between experience and the switch are unclear. Here we show a new role for the transcriptional repressor REST in the developmental switch of synaptic NMDARs. REST is activated at a critical window of time and acts via epigenetic remodeling to repress Grin2b expression and alter NMDAR properties at rat hippocampal synapses. Knockdown of REST in vivo prevented the decline in GluN2B and developmental switch in NMDARs. Maternal deprivation impaired REST activation and acquisition of the mature NMDAR phenotype. Thus, REST is essential for experience-dependent fine-tuning of genes involved in synaptic plasticity.

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Figure 1: REST increases transiently, is recruited to and coincides with epigenetic marks of repression at the Grin2b promoter during rat hippocampal postnatal development.
Figure 2: Transient increase in REST precedes the switch in NMDAR phenotype in rat dentate gyrus.
Figure 3: RNAi-mediated knockdown of REST increases Grin2b mRNA and alters NMDAR properties.
Figure 4: Rest knockdown prevents acquisition of the mature NMDAR phenotype.
Figure 5: Maternal deprivation disrupts the increase in REST, epigenetic remodeling and decrease in GluN2B during postnatal development.
Figure 6: Maternal deprivation impairs acquisition of the mature NMDAR phenotype at synapses.

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Acknowledgements

This work was supported by US National Institutes of Health grants to R.S.Z. (R01 NS46742 and NS20752) and P.E.C. (R01 MH081935) and support from the F.M. Kirby Foundation. A.E.C. was supported by a Ruth L Kirschstein Award from the US National Institute of Neurological Disorders and Stroke (F32NS071821). We thank K.-M. Noh (Albert Einstein College of Medicine) for providing the shRNA REST lentiviral construct, and A. Etgen and all the members of the Zukin and Castillo laboratories for their constructive comments on the data and the manuscript.

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  1. Alma Rodenas-Ruano and Andrés E Chávez: These authors contributed equally to this work.

Authors and Affiliations

  1. Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, USA

    Alma Rodenas-Ruano, Andrés E Chávez, Maria J Cossio, Pablo E Castillo & R Suzanne Zukin

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  1. Alma Rodenas-Ruano
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  3. Maria J Cossio
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Contributions

A.R.-R. designed and performed all the biochemical experiments and analyzed the results. M.J.C. performed biochemical experiments. A.E.C. designed and performed all the electrophysiological experiments and analyzed the results. P.E.C. and R.S.Z. helped guide the research. A.R.-R., A.E.C., P.E.C. and R.S.Z. interpreted all the results and wrote the paper.

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Correspondence to Pablo E Castillo or R Suzanne Zukin.

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Rodenas-Ruano, A., Chávez, A., Cossio, M. et al. REST-dependent epigenetic remodeling promotes the developmental switch in synaptic NMDA receptors. Nat Neurosci 15, 1382–1390 (2012). https://doi.org/10.1038/nn.3214

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