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

Huimei Yu, Yijing Su, Jaehoon Shin, Chun Zhong, Junjie U. Guo, Yi Lan Weng, Fuying Gao, Daniel H. Geschwind, Giovanni Coppola, Guo Li Ming, Hongjun Song

Research output: Contribution to journalArticlepeer-review

139 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)836-843
Number of pages8
JournalNature Neuroscience
Issue number6
StatePublished - Jan 1 2015

ASJC Scopus subject areas

  • Neuroscience(all)


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