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

doi:10.1038/nn.4008

. 2015 Jun;18(6):836-43.

doi: 10.1038/nn.4008. Epub 2015 Apr 27.

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

Affiliations

¹ 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
² 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
³ 1] Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. [2] Program in Neurogenetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. [3] Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. [4] Department of Psychiatry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
⁴ 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [3] Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [4] The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [5] Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁵ 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [3] Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [4] The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

PMID: 25915473
PMCID: PMC4446239
DOI: 10.1038/nn.4008

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

Huimei Yu et al. Nat Neurosci. 2015 Jun.

. 2015 Jun;18(6):836-43.

doi: 10.1038/nn.4008. Epub 2015 Apr 27.

Authors

Affiliations

¹ 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
² 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
³ 1] Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. [2] Program in Neurogenetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. [3] Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. [4] Department of Psychiatry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
⁴ 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [3] Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [4] The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [5] Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁵ 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [3] Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [4] The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

PMID: 25915473
PMCID: PMC4446239
DOI: 10.1038/nn.4008

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.

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Figures

**Figure 1**
Synaptic activity-dependent expression of Tet3 regulates glutamatergic synaptic transmission. (a) Expression of Tet family members in response to changes of global synaptic activity. Shown are summaries of time-course analysis of mRNA expression of Tet1, 2, 3 in cultured mouse hippocampal neurons after continuous presence of TTX (1 μM) or bicuculline (20 μM). The same cultures were used for analysis of expression of three Tet genes and data was normalized to time zero for parallel cultures. Values represent mean ± s.e.m. (n = 3; *P < 0.05, ANOVA; For Tet3 plot of TTX treatment, P = 0.5 at 0 h; P = 0.00007 at 1 h; P = 0.003 at 4 h; P = 0.002 at 12 h; P = 0.03 at 24 h and P = 0.07 at 48 h; For Tet2 bucuculline treatment: P = 0.5 at 0 h; P = 0.02 at 1 h; P = 0.01 at 4 h; P = 0.006 at 12 h; P = 0.02 at 24 h and P = 0.50 at 48 h,). (b) Western blot analysis of neuronal Tet3 protein levels upon different treatments. Hippocampal neurons in culture were treated with saline, TTX (1 μM) or bicuculline (20 μM) for 4 hours, or infected with AAV to express control shRNA (sh-control), or two different shRNAs against mouse Tet3 (sh-Tet3-1, -2). Shown are cropped sample Western blot images (left; full-length blots are presented in Supplementary Figure 11) and quantification of Tet3 protein levels (right). Values represent mean ± s.e.m. (n = 3; ***P < 0.001; **P < 0.01; *P < 0.05; ANOVA; P = 0.006, vehicle vs TTX; P = 0.02, vehicle vs Bicuculline; P = 0.0002, sh-control vs sh-Tet3-2; P = 0.0003, sh-control vs sh-Tet3-1). (c) Tet3-KD neurons exhibit elevated glutamatergic synaptic transmission. Shown are sample whole-cell voltage-clamp recording traces of hippocampal neurons co-expressing EYFP and different shRNAs (left) and cumulative distribution plot of mESPC amplitudes (right). Shown in the inset is a summary of mean mESPC amplitudes. Numbers in bar graphs indicate numbers of neurons examined. Values represent mean ± s.e.m. (***P < 0.001; **P < 0.01; Kolmogorov-Smirnov test; P = 0.003, sh-control vs sh-Tet3-1; P = 0.000009, sh-control vs sh-Tet3-2). (d) Neurons overexpressing Tet3 exhibit decreased glutamatergic synaptic transmission. Same as in (c), except that neurons were transfected with vectors to express EYFP or co-express EYFP and Tet3 (Tet3 OE). Values represent mean ± s.e.m. (**P < 0.01; Kolmogorov-Smirnov test; P = 0.002, EYFP vs Tet3 OE).

**Figure 2**
DNA oxidation and base-excision repair regulates glutamatergic synaptic transmission. Same as in **Fig. 1c-d**, except that neurons were infected with AAV to co-express EYFP and shRNA against Tet1 or Tet2 (a), Tet1-CD or its enzymatic dead mutant (Tet1-mCD) (b), or treated with vehicle, ABT (50 μM), or CRT (50 μM), for 48 hours before analysis (**c-d**). Values represent mean ± s.e.m. (***P < 0.001; *P < 0.05; Kolmogorov-Smirnov test; a: P = 0.02, sh-control vs sh-Tet1 and P = 0.01, sh-control vs sh-Tet2; b: P = 0.01, EYFP vs Tet1-CD; c: P = 0.00005, vehicle vs ABT and P = 0.0005, vehicle vs CRT; d: P = 0.002, EYFP vs EYFP + CRT; P = 0.02, EYFP vs Tet1-CD; P = 0.00005, Tet1-CD vs Tet1-CD + CRT).

**Figure 3**
Tet3 signalling mediates homeostatic synaptic scaling-up of glutamatergic synaptic transmission. (**a-d**) Tet3 signalling mediates TTX-induced synaptic scaling-up. Same as in **Fig. 2**, except that different groups of neurons were treated with TTX (1 μM) for 48 hours before analyses. (e) Tet3 KD occludes retinoic acid (RA)-induced synaptic scaling-up. Neurons were infected with AAV to express different shRNAs and were treated with RA (1 μM) for 2 hours before analysis. (***P < 0.001; **P < 0.01; *P < 0.05; ^#P > 0.1; Kolmogorov-Smirnov test; a: P = 0.0003, sh-control vs sh-control + TTX; P = 0.30, sh-Tet3-1 vs sh-Tet3-1 + TTX; P = 0.12, sh-Tet3-2 vs sh-Tet3-2 + TTX; P = 0.003, sh-control vs sh-Tet3-1; P = 0.000009, sh-control vs sh-Tet3-2; b: P = 0.007, vehicle vs vehicle + TTX; P = 0.13, ABT vs ABT + TTX; P = 0.26, CRT vs CRT + TTX; P = 0.003, vehicle vs ABT; P = 0.0005, vehicle vs CRT; c: P = 0.014 EYFP vs EYFP + TTX; P = 0.24, EYFP/Tet3 OE vs EYFP/Tet3 + TTX; P = 0.01 EYFP vs EYFP/Tet3 OE; d: P = 0.04, EYFP vs EYFP + TTX; P = 0.19, Tet1-CD vs Tet1-CD + TTX; P = 0.02, Tet1-mCD vs Tet1-mCD + TTX; P = 0.01, EYFP vs TET1-CD; e: P= 0.001, sh-control vs sh-control + RA; P = 0.37, sh-Tet3-1 vs sh-Tet3-1 + RA; P = 0.003, sh-control vs sh-Tet3-1).

**Figure 4**
Tet3 signalling mediates bicuculline-induced homeostatic synaptic scaling-down of glutamatergic synaptic transmission. Same as in **Fig. 3a-d**, except that different groups of neurons were treated with bicuculline (20 μM) for 48 hours before analyses. (***P < 0.001; **P < 0.01; *P < 0.05; ^#P > 0.1; Kolmogorov-Smirnov test; a: P = 0.03, EYFP vs EYFP + Bicu; P = 0.42, EYFP/Tet3 OE vs EYFP/Tet3 OE + Bicu; P = 0.01, EYFP vs EYFP/Tet3 OE; b: P = 0.05, EYFP vs EYFP + Bicu; P = 0.28, Tet1-CD vs Tet1-CD + Bicu; P = 0.005, Tet1-mCD vs Tet1-mCD + Bicu; P = 0.01, EYFP vs Tet1-CD; c: P = 0.01, sh-control vs sh-control + Bicu; P = 0.15, sh-Tet3-1 vs sh-Tet3-1 + Bicu; P = 0.41, sh-Tet3-2 vs sh-Tet3-2 + Bicu; P = 0.00001, sh-control vs sh-Tet3-2; d: P = 0.003, vehicle vs vehicle + Bicu; P = 0.13, ABT vs ABT + Bicu; P = 0.20, CRT vs CRT + Bicu; P = 0.003, vehicle vs ABT; P = 0.0005, vehicle vs CRT).

**Figure 5**
Tet3 signalling regulates neuronal surface GluR1 levels. (a) Tet3 knockdown increases surface GluR1 levels and prevents further changes upon TTX (1 μM) or bicuculline (20 μM) treatment for 48 hours. Shown are sample confocal images of surface GluR1 immunostaining (left, scale bar: 10 μm) and quantification (right). Signal intensity of each condition was normalized to that of neurons expressing sh-control vehicle treatment in parallel cultures. Values represent mean ± s.e.m. (n = 3; *P < 0.05; ^#P > 0.1; ANOVA). (b) Expression of Tet1-CD, but not Tet1-mCD, decreases surface GluR1 levels and prevents further changes upon TTX or bicuculline treatment. Same as in (a), except that neurons were infected with AAV to express EYFP, Tet1-CD or Tet1-mCD. (c) Western blot analyses of surface GluR1 levels under different conditions. Same as in (ab), except that surface biotinylated GluR1 proteins were examined by Western blot and quantified. Full-length blots are presented in Supplementary Figure 11. Values represent mean ± s.e.m. (n = 3; *P < 0.05; ^#P > 0.1; ANOVA) (a: P = 0.000001, sh-control vs sh-control + TTX; P = 0.000001, sh-control vs sh-control + Bicu; P = 0.30, sh-Tet3-1 vs sh-Tet3-1 + TTX; P = 0.38, sh-Tet3-1 vs sh-Tet3-1 + Bicu; P =0.20 sh-Tet3-2 vs sh-Tet3-2 + TTX; P = 0.42, sh-Tet3-2 vs sh-Tet3-2 +Bicu; P = NN-A50510B 0.0000001, sh-control vs sh-Tet3-1; P = 0.00000001, sh-control vs sh-Tet3-2; b: P = 0.00000001, EYFP vs EYFP + TTX; P = 0.0000001, EYFP vs EYFP + Bicu; P = 0.25, Tet1-CD vs Tet1-CD + TTX; P = 0.43, Tet1-CD vs Tet1-CD + Bicu; P = 0.00000001, Tet1-mCD vs Tet1-mCD + TTX; P = 0.00000001, Tet1-mCD vs Tet1-mCD + Bicu; c: P = 0.03, sh-control vs sh-control + TTX; P = 0.01, sh-control vs sh-control + Bicu; P = 0.38, sh-Tet3-2 vs sh-Tet3-2 + TTX; P = 0.09, sh-Tet3-2 vs sh-Tet3-2 +Bicu; P = 0.27, Tet1-CD vs Tet1-CD + TTX; P = 0.12, Tet1-CD vs Tet1-CD + Bicu; P = 0.004, sh-control vs sh-Tet3-2; P = 0.02, sh-control vs Tet1-CD)

**Figure 6**
Tet3 regulates gene expression in neurons in response to global synaptic activity changes. (a) Comparison of gene expression in neurons expressing sh-control or sh-Tet3-2 by RNA-seq analyses. Shown is a summary dot plot, with red dots representing up-regulated genes and blue dots representing down-regulated genes (n = 3 samples each; False Discover Rate (FDR) < 0.05). (b) Venn diagrams of differentially expressed genes at 4 hours upon TTX (1 μM) or bicuculline (20 μM) treatment in neurons expressing sh-control or sh-Tet3-2 based on RNA-seq analyses (FDR < 0.05). (**c-d**) Box-plot of mean expression levels of up- and down-regulated genes in neurons expressing sh-control in response to TTX (c) or bicuculline (d) treatment and the expression of the same sets of genes in Tet3-KD neurons under the same condition (Wilcoxon Rank Sum test: c: P = 2.2e⁻¹⁶, upregulated genes; P = 14.2e⁻¹⁴ down regulated genes d: P < 2.2e-, both upregulated and down regulated genes.

**Figure 7**
Essential role of Tet3 in neuronal activity-induced DNA methylation dynamics at the *Bdnf IV* promoter region and gene expression. (**a-b**) Bisulfite sequencing analysis of control, Tet3-KD, or Tet1-CD neurons at 4 hours after treatment of saline, TTX or bicuculline. Sample bisulfite sequencing results at the *Bdnf* promoter IV and *Fgf1G* promoter regions are shown (a). Each row represents one allele showing methylation status of individual CpG sites (open circle: unmethylated; closed circle methylated). Mean values of methylate levels of all CpG sites for each region are also shown for each individual culture. A summary of results from multiple cultures is also shown (b). A minimum of 15 alleles was examined for DNA methylation for each culture. Values represent mean ± s.e.m. (n = 3-6 cultures; *P < 0.05; ^#P > 0.1; ANOVA; *Bdnf IV*: P = 0.0006, sh-control vs sh-control + TTX; P = 0.007, control vs control + Bicu; P = 0.10, sh-Tet3-2 vs sh-Tet3-2 + TTX; P = 0.32, sh-Tet3-2 vs sh-Tet3-2 + Bicu; P = 0.30, Tet1-CD vs Tet1-CD + TTX; P = 0.37, Tet1-CD vs Tet1-CD + Bicu; P = 0.03, control vs sh-Tet3-2; P = 0.02, control vs Tet1-CD). (c) ChIP-PCR analyses of Tet3 binding to *Bdnf IV* and *Fgf1G* promoter regions. Flag-tagged Tet3 was expressed in hippocampal neurons for analysis. Full-length blots are presented in Supplementary Figure 11. (d) Summary of mRNA expression under different conditions. Values represent mean ± s.e.m. (n = 3 cultures; *P < 0.05; ^#P > 0.1; ANOVA; *Bdnf IV*: P = 0.0006, sh-control vs sh-control + TTX; P = 0.01, sh-control vs sh-control + Bicu; P = 0.16, sh-Tet3-2 vs sh-Tet3-2 + TTX; P = 0.07, sh-Tet3-2 vs sh-Tet3-2 +Bicu; P = 0.30, Tet1-CD vs Tet1-CD + TTX; P = 0.10, Tet1-CD vs Tet1-CD + Bicu; P = 0.00004, sh-control vs sh-Tet3-2; P = 0.02, sh-control vs Tet1-CD).

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References

1. Tsankova N, Renthal W, Kumar A, Nestler EJ. Epigenetic regulation in psychiatric disorders. Nature reviews. Neuroscience. 2007;8:355–367. - PubMed
1. Graff J, Kim D, Dobbin MM, Tsai LH. Epigenetic regulation of gene expression in physiological and pathological brain processes. Physiol Rev. 2011;91:603–649. - PubMed
1. Telese F, Gamliel A, Skowronska-Krawczyk D, Garcia-Bassets I, Rosenfeld MG. “Seq-ing” insights into the epigenetics of neuronal gene regulation. Neuron. 2013;77:606–623. - PMC - PubMed
1. Shin J, Ming GL, Song H. DNA modifications in the mammalian brain. Philosophical transactions of the Royal Society of London. Series B, Biological sciences. 2014;369 doi:10.1098/rstb.2013.0512. - PMC - PubMed
1. Day JJ, Kennedy AJ, Sweatt JD. DNA methylation and its implications and accessibility for neuropsychiatric therapeutics. Annual review of pharmacology and toxicology. 2015;55:591–611. doi:10.1146/annurev-pharmtox-010814-124527. - PMC - PubMed

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[1] Tsankova N, Renthal W, Kumar A, Nestler EJ. Epigenetic regulation in psychiatric disorders. Nature reviews. Neuroscience. 2007;8:355–367. - PubMed

[2] Tsankova N, Renthal W, Kumar A, Nestler EJ. Epigenetic regulation in psychiatric disorders. Nature reviews. Neuroscience. 2007;8:355–367. - PubMed

[3] Graff J, Kim D, Dobbin MM, Tsai LH. Epigenetic regulation of gene expression in physiological and pathological brain processes. Physiol Rev. 2011;91:603–649. - PubMed

[4] Graff J, Kim D, Dobbin MM, Tsai LH. Epigenetic regulation of gene expression in physiological and pathological brain processes. Physiol Rev. 2011;91:603–649. - PubMed

[5] Telese F, Gamliel A, Skowronska-Krawczyk D, Garcia-Bassets I, Rosenfeld MG. “Seq-ing” insights into the epigenetics of neuronal gene regulation. Neuron. 2013;77:606–623. - PMC - PubMed

[6] Telese F, Gamliel A, Skowronska-Krawczyk D, Garcia-Bassets I, Rosenfeld MG. “Seq-ing” insights into the epigenetics of neuronal gene regulation. Neuron. 2013;77:606–623. - PMC - PubMed

[7] Shin J, Ming GL, Song H. DNA modifications in the mammalian brain. Philosophical transactions of the Royal Society of London. Series B, Biological sciences. 2014;369 doi:10.1098/rstb.2013.0512. - PMC - PubMed

[8] Shin J, Ming GL, Song H. DNA modifications in the mammalian brain. Philosophical transactions of the Royal Society of London. Series B, Biological sciences. 2014;369 doi:10.1098/rstb.2013.0512. - PMC - PubMed

[9] Day JJ, Kennedy AJ, Sweatt JD. DNA methylation and its implications and accessibility for neuropsychiatric therapeutics. Annual review of pharmacology and toxicology. 2015;55:591–611. doi:10.1146/annurev-pharmtox-010814-124527. - PMC - PubMed

[10] Day JJ, Kennedy AJ, Sweatt JD. DNA methylation and its implications and accessibility for neuropsychiatric therapeutics. Annual review of pharmacology and toxicology. 2015;55:591–611. doi:10.1146/annurev-pharmtox-010814-124527. - PMC - PubMed

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

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

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