Synaptic plasticity is modulated by changes in gene expression, which are regulated by numerous epigenetic mechanisms in neuropsychiatric diseases [1]. With the advancement of experimental approaches, the neurosciences have gained incredible insights into additional macromolecular modifiers, transforming our perspectives on how synaptic plasticity can be shaped in homeostatic and disease conditions. Specifically, nucleic acid modifications that have been recently shown to affect gene expression are RNA epigenetics or, epitranscriptomics (Fig. 1). The most common RNA modification is the m6A methylation on mRNAs, accounting for ~50% of all methylated ribonucleotides. It is involved in mRNA stability, degradation, nuclear export, alternative splicing, and is highly enriched in the brain [2]. M6A methylation confers a temporal signal on targeted mRNAs that impacts the translation of their respective proteins [2], thereby affecting protein signaling, leading to dynamical alterations of cellular processes like synaptic plasticity and subsequent changes in behavior [3, 4]. Thus far, epitranscriptomic mechanisms in synaptic plasticity and behaviors are understudied. Recently, a mouse synaptic m6A epitranscriptome was made available, generated from forebrain synaptosomes [5]. The findings therein suggested that hypermethylated m6A mRNAs are functionally partitioned to both the axons and dendrites, with possible roles in regulating synaptic organization, transmission, and long-term potentiation. Indeed, in vitro knockdown of m6A readers YT521-B homology domain family 1 (YTHDF1) in dissociated hippocampal neurons increased dendritic spine neck length, decreased the postsynaptic density–95 occupancy of spines, yet showed no observable changes in spine density [5]. Remarkably, YTHDF1 knockout mice exhibit impaired learning, memory, and long-term potentiation and plasticity, but selective re-expression of YTHDF1 rescues their behavioral and hippocampal plasticity impairments [3]. Moreover, the temporal coordination of m6A mRNA methylation and degradation is also vital during neuroembryological development. The absence of m6A methylation on pluripotency-driving mRNAs in neural stem cells (NSC) prevents their timely degradation, resulting in disruption of cell differentiation, thus, impaired development and synaptic plasticity. Adult NSCs highly express the brain-enriched demethylase, fat mass and obesity associated (FTO) protein, whose knockout decreases proliferation and differentiation of adult NSCs, decreases brain size, and impairs learning and memory. These FTO-dependent effects may be the result of decreased brain-derived neurotrophic factor (BDNF) levels [4]. Strikingly, in human postmortem amygdala of early onset alcohol use disorder, BNDF-antisense lncRNA is hypomethylated, resulting in its increased expression and recruitment of enhancer-of-Zeste2 and histone-3 lysine-27 trimethylation (H3K27me3) at the promoter of BDNF exon 9, leading to decreased BNDF expression and levels [1]. Such results further demonstrate how m6A methylation can be intermingled with transcriptional regulation and epigenetics. Indeed, epigenetic mechanisms controlling m6A methylation have been revealed, where H3K36me3 marks are bound by the methyltransferase-like 14 subunit to recruit the m6A methyltransferase complex for deposition of methyl groups onto the DRACH (A = methylatable adenosine, D = A, G or U, R = A or G, and H = A, C or U) consensus sequences of transcribing mRNAs [6]. In summary, these examples highlight the richness of epitranscriptomics and call for the attention of neuroscientists to investigate how various steps of this process interact with genomic and epigenomic mechanisms to regulate synaptic plasticity, structure, and behavior in psychiatric disorders like addiction (Fig. 1).

Fig. 1: Synaptic plasticity and behavior are altered upon exposure to environmental factors.
figure 1

Such changes may be the result of complex genomic, epigenomic, and epitranscriptomic regulatory mechanisms. This simplified schematic highlights the basic biology and components of m6A epitranscriptomics that could be affected in disorders, providing a working guide for future investigations. Normally, the m6A methyltransferase complex, composed of METTL3, METTL14, Wilm’s tumor 1-associating protein (WTAP), and other ancillary subunits not shown, is signaled by H3K36me3 to deposit methyl (Me) groups onto DRACH consensus sequences of transcribing mRNAs. This complex can also deposit methyl groups onto other forms of RNA such as the aforementioned BDNF-antisense lncRNA. The m6A modification is reversible through two principal demethylases, FTO and AlkB Homolog 5 (ALKBH5). Modified mRNAs are read by YT521-B homology domain containing 1 (YTHDC1) for nuclear export, after which they temporally encounter cytosolic readers YTHDF1-3 in the prevailing reader model, where YTHDF1/3 promote translation and YTHDF2/3 promote degradation [2]. These functions have been elucidated using genetic in vitro and in vivo experiments. Figure is prepared using BioRender.

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