Memory and neuromodulation: A perspective of DNA methylation

Highlights

• Neuromodulation enhances cognition through altered methylation profile.

• DNMTs, MeCP2 and DNA demethylases are major components underlying neuromodulation effects.

• Neuroepigentic studies are warranted to characterize diverse effects of neuromodulation on memory.

Abstract

Neuromodulation techniques have shown promising efficacy on memory function and understanding the epigenetic mechanisms contributing to these processes would shed light on the molecular outcomes essential for cognition. In this review, we highlight some epigenetic mechanisms underlying neuromodulation and regulatory effects of neuronal activity-induced DNA methylation on genes that are highly involved in memory formation. Next, we examine the evidence to support DNA methyltransferase 3a, methyl-CpG binding protein 2, and DNA demethylase as possible memory modulation targets. Finally, we report the recent developments in the field of neuromodulation and explore the potential of these techniques for future neuroepigenetic research.

Introduction

In recent years, neuroscientists have made significant progress in elucidating how memory is formed in the complex neural network. One of the current hypotheses of memory formation suggests that genes are divided into memory-suppressing and memory-enhancing genes. For memory consolidation to occur, memory-suppressing genes are transcriptionally inactivated, whereas memory-enhancing genes are expressed, thus tilting the balance towards the expression of memory-enhancing proteins (Abel and Kandel, 1998). Memory formation starts with a transient external stimulus, which then becomes sustained over a relatively long period of time, even throughout one’s lifetime. The stimulus must be able to induce certain molecular and cellular responses robustly and persistently to maintain these effects. One of the many hypotheses in memory research suggest that the memory relies on the stimulus resulting in perpetual gene transcription and protein expression, as the major effectors of the cellular responses. After Bliss and Lomo’s discovery in 1973 of long-term potentiation (LTP) that explained how synaptic transmission mediated memory formation, researchers have been trying to answer the question of how memories propagate (Bliss and Lomo, 1973). Eric Kandel and his team, who are pioneers in the field, discovered that during the late phase of LTP (L-LTP), which is recognized as the prerequisite of long-term memory formation, gene transcription becomes necessary, as shown by the subsequent activation of cAMP-response element binding (CREB) protein, a transcription factor that mediates the expression of genes that facilitate L-LTP (Kandel, 2001). Recent studies suggest that DNA methyltransferase (DNMT) is required in the early induction of LTP in the hippocampus, and the subsequent methylation of certain genes may mediate memory formation (Levenson et al., 2006; Miller and Sweatt, 2007). Given the bidirectional control it exerts on gene expressions, DNA methylation is thought to serve as the driving force of upregulating the transcription of memory-enhancing genes such as brain-derived neurotrophic factor (Bdnf), reelin and activity-regulated cytoskeleton-associated protein (Arc) while reducing the production of memory-suppressing gene transcripts such as calcineurin (CaN) and protein phosphatase 1 (PP1) (see below). These changes are often accompanied by altered expressions of DNMTs and DNA demethylases, and they are essential to successful memory formation. In light of this, memory researchers have invested much effort into investigating epigenetic mechanisms of how gene expression modulates behavior and memory propagation, which has given rise to the subfield in epigenetics called neuroepigenetics (Day and Sweatt, 2011).

DNA methylation, which governs a wide array of gene expressions in a self-perpetuating manner, contributes to various cellular functions. Research from the past decades has contributed to an increasing body of evidence that suggests the intricate epigenetic network may serve as the foundation of cellular events contributing to memory formation. However, the temporal and regional specificity of DNA methylation in the neural circuitry remains a concern in memory research. Neuromodulatory surgical techniques, which involve the delivery of an electrical current to produce therapeutic relief, have shown immense potential in treating memory-related and neuropsychiatric disorders (Perlmutter and Mink, 2006; Merkl et al., 2009; Chang et al., 2018; Hadar et al., 2018). Given that previous studies have validated the ability of neuronal activity to effectively alter DNA methylation (Nelson et al., 2008; Guo et al., 2011a), it is reasonable that researchers would begin to explore the mechanism of neuromodulation techniques, such as transcranial direct current stimulation (tDCS) (Podda et al., 2016), electroconvulsive therapy (ECT) (Ma et al., 2009), vagus nerve stimulation (VNS) (Sanders et al., 2019), and deep brain stimulation (DBS) (Pohodich et al., 2018), from an epigenetic perspective. By researching these neuromodulation techniques in in vitro studies that mimic cellular changes under neuronal activity, we can gain important insights on the potential therapeutic application of these current methods. The therapeutic effects of neuromodulation techniques have been shown to be mediated by epigenetic mechanisms. A deeper understanding of the underlying epigenetic mechanism of these techniques may pave way for their application in neurological disorders associated with epigenetics. In this review, we highlight the major findings in neuroepigenetic research, which have revealed the intertwined network connecting DNA methylation and cognitive abilities. We also discuss DNA methyltransferase 3a (DNMT3a), methyl-CpG binding protein 2 (MeCP2), and DNA demethylase, which are three components highly involved in DNA methylation-dependent epigenetic regulation. Lastly, we discuss how neuromodulation holds much promise as an epigenetic modulator, and examine the current research to gain insights that may help to further clarify the role of DNA methylation in memory modulation.