Research ArticleNeuronal Plasticity

Dynamic DNA methylation regulates neuronal intrinsic membrane excitability

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Science Signaling  23 Aug 2016:
Vol. 9, Issue 442, pp. ra83
DOI: 10.1126/scisignal.aaf5642

Setting intrinsic excitability with epigenetics

The responsiveness of a neuron to stimuli is called the intrinsic membrane excitability. Various neuropsychiatric and neurological diseases are associated with altered intrinsic membrane excitability. Meadows et al. showed that epigenetic changes in the DNA contribute to the intrinsic excitability of cortical neurons. Inhibition of the methylation of cytosines in the DNA of cultured cortical neurons enhanced their intrinsic membrane excitability so that the neurons generated more action potentials in response to a stimulus. The increase in excitability required enzymatic demethylation of the cytosines and transcription. Electrophysiological analysis revealed that the increased excitability could be explained by reduced activity of a specific potassium channel, and inhibiting this channel pharmacologically produced the same enhancement of intrinsic membrane excitability as produced by inhibiting DNA cytosine methylation. Thus, epigenetic remodeling of DNA controls neuronal activity by altering the electrophysiological properties of the entire neuron as well as mediating changes localized to the synapse. This study has implications for neuropsychiatric and neurological disorders associated with alterations in intrinsic plasticity, such as epilepsy, neuropathic pain, anxiety, depression, drug addiction, and Alzheimer’s disease.


Epigenetic modifications, such as DNA cytosine methylation, contribute to the mechanisms underlying learning and memory by coordinating adaptive gene expression and neuronal plasticity. Transcription-dependent plasticity regulated by DNA methylation includes synaptic plasticity and homeostatic synaptic scaling. Memory-related plasticity also includes alterations in intrinsic membrane excitability mediated by changes in the abundance or activity of ion channels in the plasma membrane, which sets the threshold for action potential generation. We found that prolonged inhibition of DNA methyltransferase (DNMT) activity increased intrinsic membrane excitability of cultured cortical pyramidal neurons. Knockdown of the cytosine demethylase TET1 or inhibition of RNA polymerase blocked the increased membrane excitability caused by DNMT inhibition, suggesting that this effect was mediated by subsequent cytosine demethylation and de novo transcription. Prolonged DNMT inhibition blunted the medium component of the after-hyperpolarization potential, an effect that would increase neuronal excitability, and was associated with reduced expression of the genes encoding small-conductance Ca2+-activated K+ (SK) channels. Furthermore, the specific SK channel blocker apamin increased neuronal excitability but was ineffective after DNMT inhibition. Our results suggested that DNMT inhibition enables transcriptional changes that culminate in decreased expression of SK channel–encoding genes and decreased activity of SK channels, thus providing a mechanism for the regulation of neuronal intrinsic membrane excitability by dynamic DNA cytosine methylation. This study has implications for human neurological and psychiatric diseases associated with dysregulated intrinsic excitability.

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