Tet3 regulates synaptic transmission and homeostatic plasticity via DNA oxidation and repair

Nat Neurosci. 2015 Jun;18(6):836-43. doi: 10.1038/nn.4008. Epub 2015 Apr 27.

Abstract

Contrary to the long-held belief that DNA methylation of terminally differentiated cells is permanent and essentially immutable, post-mitotic neurons exhibit extensive DNA demethylation. The cellular function of active DNA demethylation in neurons, however, remains largely unknown. Tet family proteins oxidize 5-methylcytosine to initiate active DNA demethylation through the base-excision repair (BER) pathway. We found that synaptic activity bi-directionally regulates neuronal Tet3 expression. Functionally, knockdown of Tet or inhibition of BER in hippocampal neurons elevated excitatory glutamatergic synaptic transmission, whereas overexpressing Tet3 or Tet1 catalytic domain decreased it. Furthermore, dysregulation of Tet3 signaling prevented homeostatic synaptic plasticity. Mechanistically, Tet3 dictated neuronal surface GluR1 levels. RNA-seq analyses further revealed a pivotal role of Tet3 in regulating gene expression in response to global synaptic activity changes. Thus, Tet3 serves as a synaptic activity sensor to epigenetically regulate fundamental properties and meta-plasticity of neurons via active DNA demethylation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA / metabolism*
  • DNA Methylation
  • DNA Repair / physiology*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Gene Knockdown Techniques
  • Homeostasis / physiology*
  • In Vitro Techniques
  • Mice
  • Mice, Inbred C57BL
  • Neuronal Plasticity / genetics
  • Neuronal Plasticity / physiology
  • Oxidation-Reduction
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology*
  • Receptors, AMPA / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Synaptic Transmission / physiology*

Substances

  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • Receptors, AMPA
  • DNA
  • Tet3 protein, mouse
  • glutamate receptor ionotropic, AMPA 1

Associated data

  • GEO/GSE67245