Experience‐dependent neural plasticity, learning, and memory in the era of epitranscriptomics

Abstract

In this short review, we highlight recent findings in the emerging field of epitranscriptomic mechanisms and discuss their potential role in neural plasticity, learning and memory. These include the influence of RNA modifications on activity-induced RNA structure states, RNA editing and RNA localization, and how qualitative state changes in RNA increase the functional diversity and information-carrying capacity of RNA molecules. We predict that RNA modifications may be just as important for synaptic plasticity and memory as quantitative changes in transcript and protein abundance, but with the added advantage of not being required to signal back to the nucleus, and therefore better suited to be coordinated with the temporal dynamics of learning.

Intrinsic mechanisms of neuronal axon regeneration

“…Cell-type-specific responses may also result from other mechanisms, such as post-transcriptional modification of RNA, that affect gene expression (and are referred to as ) 100 . Because RNA modifications were proposed to affect activity-induced RNA editing and localization in the brain 101 and are known to affect cortical development 102 , it is likely that RNA modifications have an important role in axon regeneration. Indeed, nerve injury was recently shown to induce an increase in N6-methyladenosine, the most abundant modification of mRNA, in transcripts encoding many RAGs, and deletion of the enzymes responsible for this epitranscriptomic mark was shown to reduce axon regeneration in the PNS 103 .…”

The role of mRNA m6A methylation in the nervous system

“…In the emerging field of epitranscriptomic mechanisms, mRNA m 6 A modification has potential role in learning and memory [77]. It regulates physiological and stressinduced behavior in the adult mammalian brain, and augments the strength of weak memories [78][79][80].…”

“…The m 6 A modification plays a key role in synaptic regeneration of mature mouse neurons. Increased m 6 A in somatic neurons alters the transcriptome response to synaptic plasticity [77,89]. The m 6 A methylation of neurological function-related genes in the hippocampus of human immunodeficiency virus transgenic rats is significantly different, suggesting synaptic damage and neurodegeneration [95].…”

Hippocampal knockdown of Piwil1 and Piwil2 enhances contextual fear memory in mice

“…Learning-related neuronal plasticity and the formation of memory depend on tightly controlled patterns of gene expression, with non-coding RNAs (ncRNAs) emerging as an essential regulatory mechanism in this process (Bredy, Lin, Wei, Baker-Andresen, and Mattick, 2011;Leighton, Ke, Zajaczkowski, Edmunds, Spitale, and Bredy, 2017;Spadaro and Bredy, 2012). Non-coding RNAs are diverse in size, structure, origin and function; small ncRNAs, in particular, arise through a number of distinct biogenesis pathways, are categorised into several distinct classes, and primarily serve to finetune gene expression in response to current environmental demands.…”