Activity-dependent Suppression of Miniature Neurotransmission Through the Regulation of DNA Methylation

Overview

Journal J Neurosci

Specialty Neurology

Date 2008 Jan 11

PMID 18184782

Citations 137

Authors

Erika D Nelson

Ege T Kavalali

Lisa M Monteggia

Affiliations

Soon will be listed here.

Abstract

DNA methylation is an epigenetic mechanism that plays a critical role in the repression of gene expression. Here, we show that DNA methyltransferase (DNMT) inhibition in hippocampal neurons results in activity-dependent demethylation of genomic DNA and a parallel decrease in the frequency of miniature EPSCs (mEPSCs), which in turn impacts neuronal excitability and network activity. Treatment with DNMT inhibitors reveals an activity-driven demethylation of brain-derived neurotrophic factor promoter I, which is mediated by synaptic activation of NMDA receptors, because it is susceptible to AP-5, a blocker of NMDA receptors. The specific effect of DNMT inhibition on spontaneous excitatory neurotransmission requires gene transcription and is occluded in the absence of the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2). Interestingly, enhancing excitatory activity, in the absence of DNMT inhibitors, also produces similar decreases in DNA methylation and mEPSC frequency, suggesting a role for DNA methylation in the control of homeostatic synaptic plasticity. Furthermore, adding excess substrate for DNA methylation (S-adenosyl-L-methionine) rescues the suppression of mEPSCs by DNMT inhibitors in wild-type neurons, as well as the defect seen in MeCP2-deficient neurons. These results uncover a means by which NMDA receptor-mediated synaptic activity drives DNA demethylation within mature neurons and suppresses basal synaptic function.

Citing Articles

Delving Into the Interaction Between Exercise and Diabetes on Methylation of the FKBP5 Gene.

Yang T, Tsai J, Hsu H, Chen Y, Liaw Y, Hsu S J Diabetes Res. 2025; 2025:1162708.

PMID: 40017583 PMC: 11865466. DOI: 10.1155/jdr/1162708.

Brain-derived neurotrophic factor scales presynaptic calcium transients to modulate excitatory neurotransmission.

Wang C, McCarthy C, Guzikowski N, Kavalali E, Monteggia L Proc Natl Acad Sci U S A. 2024; 121(17):e2303664121.

PMID: 38621124 PMC: 11047077. DOI: 10.1073/pnas.2303664121.

Insights into epileptogenesis from post-traumatic epilepsy.

Pease M, Gupta K, Moshe S, Correa D, Galanopoulou A, Okonkwo D Nat Rev Neurol. 2024; 20(5):298-312.

PMID: 38570704 DOI: 10.1038/s41582-024-00954-y.

Abnormal DNA methylation within HPA-axis genes years after paediatric critical illness.

Coppens G, Vanhorebeek I, Guiza F, Derese I, Wouters P, Teblick A Clin Epigenetics. 2024; 16(1):31.

PMID: 38395991 PMC: 10893716. DOI: 10.1186/s13148-024-01640-y.

Differential usage of DNA modifications in neurons, astrocytes, and microglia.

Tooley K, Chucair-Elliott A, Ocanas S, Machalinski A, Pham K, Hoolehan W Epigenetics Chromatin. 2023; 16(1):45.

PMID: 37953264 PMC: 10642035. DOI: 10.1186/s13072-023-00522-6.

References

McKinney R, Capogna M, Durr R, Gahwiler B, Thompson S . Miniature synaptic events maintain dendritic spines via AMPA receptor activation. Nat Neurosci. 1999; 2(1):44-9. DOI: 10.1038/4548. View

Desai N, Rutherford L, Turrigiano G . BDNF regulates the intrinsic excitability of cortical neurons. Learn Mem. 1999; 6(3):284-91. PMC: 311300. View

Amir R, Van den Veyver I, Wan M, Tran C, Francke U, Zoghbi H . Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999; 23(2):185-8. DOI: 10.1038/13810. View

Kavalali E, Klingauf J, Tsien R . Activity-dependent regulation of synaptic clustering in a hippocampal culture system. Proc Natl Acad Sci U S A. 1999; 96(22):12893-900. PMC: 23151. DOI: 10.1073/pnas.96.22.12893. View

Hansen R, Wijmenga C, Luo P, Stanek A, Canfield T, Weemaes C . The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc Natl Acad Sci U S A. 1999; 96(25):14412-7. PMC: 24450. DOI: 10.1073/pnas.96.25.14412. View

Robertson K, Jones P . DNA methylation: past, present and future directions. Carcinogenesis. 2000; 21(3):461-7. DOI: 10.1093/carcin/21.3.461. View

Inano K, Suetake I, Ueda T, Miyake Y, Nakamura M, Okada M . Maintenance-type DNA methyltransferase is highly expressed in post-mitotic neurons and localized in the cytoplasmic compartment. J Biochem. 2000; 128(2):315-21. DOI: 10.1093/oxfordjournals.jbchem.a022755. View

Reik W, Dean W, Walter J . Epigenetic reprogramming in mammalian development. Science. 2001; 293(5532):1089-93. DOI: 10.1126/science.1063443. View

HARATA N, Pyle J, Aravanis A, Mozhayeva M, Kavalali E, Tsien R . Limited numbers of recycling vesicles in small CNS nerve terminals: implications for neural signaling and vesicular cycling. Trends Neurosci. 2001; 24(11):637-43. DOI: 10.1016/s0166-2236(00)02030-0. View

10.

Shahbazian M, Antalffy B, Armstrong D, Zoghbi H . Insight into Rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation. Hum Mol Genet. 2002; 11(2):115-24. DOI: 10.1093/hmg/11.2.115. View

11.

Mozhayeva M, Sara Y, Liu X, Kavalali E . Development of vesicle pools during maturation of hippocampal synapses. J Neurosci. 2002; 22(3):654-65. PMC: 6758530. View

12.

Kilman V, van Rossum M, Turrigiano G . Activity deprivation reduces miniature IPSC amplitude by decreasing the number of postsynaptic GABA(A) receptors clustered at neocortical synapses. J Neurosci. 2002; 22(4):1328-37. PMC: 6757564. View

13.

Carter A, Regehr W . Quantal events shape cerebellar interneuron firing. Nat Neurosci. 2002; 5(12):1309-18. DOI: 10.1038/nn970. View

14.

Jaenisch R, Bird A . Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003; 33 Suppl:245-54. DOI: 10.1038/ng1089. View

15.

Ehrlich M . Expression of various genes is controlled by DNA methylation during mammalian development. J Cell Biochem. 2003; 88(5):899-910. DOI: 10.1002/jcb.10464. View

16.

Meehan R, Lewis J, Bird A . Characterization of MeCP2, a vertebrate DNA binding protein with affinity for methylated DNA. Nucleic Acids Res. 1992; 20(19):5085-92. PMC: 334288. DOI: 10.1093/nar/20.19.5085. View

17.

Chen W, Chang Q, Lin Y, Meissner A, West A, Griffith E . Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science. 2003; 302(5646):885-9. DOI: 10.1126/science.1086446. View

18.

Martinowich K, Hattori D, Wu H, Fouse S, He F, Hu Y . DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science. 2003; 302(5646):890-3. DOI: 10.1126/science.1090842. View

19.

Sutton M, Wall N, Aakalu G, Schuman E . Regulation of dendritic protein synthesis by miniature synaptic events. Science. 2004; 304(5679):1979-83. DOI: 10.1126/science.1096202. View

20.

Noh J, Sharma R, Veldic M, Salvacion A, Jia X, Chen Y . DNA methyltransferase 1 regulates reelin mRNA expression in mouse primary cortical cultures. Proc Natl Acad Sci U S A. 2005; 102(5):1749-54. PMC: 547890. DOI: 10.1073/pnas.0409648102. View