Dynamic DNA methylation regulates neuronal intrinsic membrane excitability

Abstract

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.

Memory formation depends on both synapse-specific modifications of synaptic strength and cell-specific increases in excitability

“…That important function may rely on stable changes at the synapse (but see refs. 62,63 ) or on learning-related transcriptional changes other than those mediated by CREB 64,65 (for the potential utility of hypothesized long-term changes in excitability, see ref. 66 ).…”

Memory Erasure Experiments Indicate a Critical Role of CaMKII in Memory Storage

“…Indeed, there is now evidence for epigenetic and transcriptional regulatory processes that control learning-dependent changes, including global changes in cellular excitability (Abel and Klann, 2013; Meadows et al, 2016; Yiu et al, 2014; Zhou et al, 2009). Thus, both cell-wide and synapse-specific processes may be necessary for memory storage (J. Lisman and A. Silva; in preparation).…”

Cross-species epigenetic regulation of nucleus accumbens KCNN3 transcript variants by excessive ethanol drinking and dependence

“…Although it is unknown if heavy ethanol drinking in macaques alters firing properties of NAcC MSNs, the shift in transcript variants and the reduction in total KCa2 channel protein suggests that prolonged ethanol intake will increase intrinsic excitability similar to results from rodent models of ethanol self-administration (11) and dependence (13,78). In addition to reduced Kcnn3 gene expression and increased intrinsic excitability, a recent study reported a loss of apamin's ability to increase evoked firing in cultured cortical neurons treated with DNA methyltransferase inhibitors (33). Thus, these data provide support that the increase 20 in SK3_ex1B and SK3_ex4 TV expression through hypermethylation of KCNN3 exon 1A is an underlying mechanism driving these functional and behavioral adaptations across species and brain regions.…”

“…DNA methylation (DNAm) is an epigenetic mark that can contribute to modulation of gene expression by modifying the compaction status of the chromatin. Alterations in DNA methylation are reported in heavy drinking monkeys and rodents (30)(31)(32), and a recent study demonstrated that knockdown of DNA methyltransferases reduced Kcnn3 expression and increased intrinsic excitability of cultured cortical neurons (33). Thus, we measured DNAm levels at a differentially methylated region (DMR) in exon 1 that coincides with a cross-species regulatory region within the KCNN3 promoter.…”