MicroRNA regulation of neural plasticity and memory

Abstract

MicroRNAs (miRNAs) are a class of endogenous, small non-coding RNAs that mediate post-transcriptional gene silencing by complementary binding to the 3′untranslated region of target mRNAs. The transient and localized expression of these small RNAs in dendrites, their capacity to respond in an activity-dependent manner, and the observation that a single miRNA can simultaneously regulate many genes, make brain-specific miRNAs ideal candidates for the fine-tuning of gene expression associated with neural plasticity and memory formation. Here we provide an overview of the current literature, which supports the proposal that non-coding RNA-mediated regulation of gene function represents an important, yet underappreciated, layer of epigenetic control that contributes to learning and memory in the adult brain.

Introduction

It is known that both embryonic development and mature brain function are dependent on epigenetic processes, which involve the methylation and hydroxymethylation of cytosine in genomic DNA, as well as a myriad of different modifications at various histone lysine residues at hundreds of thousands of different positions in the nucleosome of different cells at different developmental stages (Barski et al., 2007, Kouzarides, 2007). Over recent years it has become evident that epigenetic mechanisms make important contributions to the formation of memory (Day & Sweatt, 2011). Increased developmental and cognitive complexity in animals also coincides with a massive increase in the extent of non-protein-coding DNA and concomitant expression of regulatory RNAs (Pheasant and Mattick, 2007, Taft et al., 2007). The mammalian genome is transcribed essentially in its entirety to produce tens, if not hundreds, of thousands of large and small regulatory RNAs (Birney et al., 2007, Carninci et al., 2005; Cheng et al., 2005, Mattick and Makunin, 2006), including microRNAs (miRNAs), that control most aspects of development at the translational level (Bartel, 2004), as well as long non-coding RNAs (lncRNAs) that fulfill a variety of developmental functions, including the formation of specialized organelles in neuronal and other differentiated cells (Amaral and Mattick, 2008, Mercer et al., 2008, Mercer et al., 2010). The central nervous system has evolved an extraordinarily complex RNA metabolism (Mehler & Mattick, 2007), with most non-coding RNAs expressed in the brain, and many in exquisitely precise patterns of expression in brain regions known to be important for cognition (Mercer et al., 2008). Superimposed on this regulatory system, humans have evolved considerable plasticity in RNA as a consequence of RNA editing, which has expanded enormously in the mammalian and especially primate lineage (Mattick, 2010). Chromatin-modifying complexes are also directed to their sites of action by non-coding regulatory RNAs, which appear to represent a previously hidden layer of regulatory programming of developmental processes (Mattick, Amaral, Dinger, Mercer, & Mehler, 2009), which may also be active in the adult brain to coordinate gene function associated with learning and memory. Indeed, recent evidence indicates that miRNAs interact with the epigenome to control plasticity in the adult brain (Gao et al., 2010).

MiRNAs are a family of endogenously expressed small regulatory RNAs that post-transcriptionally regulate gene silencing in plants, invertebrates, and mammals by inhibiting the function of their target mRNAs through complementary binding (Bartel, 2004). First identified as regulating the timing of larval development in Caenorhabditis elegans (Lee et al., 1993, Reinhart et al., 2000), the number of identified miRNAs now exceeds one hundred in invertebrates, and reaches close to one thousand in humans and mice (Chiang et al., 2010, Landgraf et al., 2007, Ruby et al., 2006, Ruby et al., 2007). A unique feature of these non-coding RNAs is their ability to bind and regulate many genes, and in some cases multiple miRNAs target similar families of genes (Friedman et al., 2009, Hendrickson et al., 2009, John et al., 2004, Krichevsky et al., 2003, Lim et al., 2005), thereby enhancing their ability to regulate plasticity in the brain. Although lncRNAs may be fundamental for regulating gene function during development, no published studies have examined their role in cognition and memory. On the contrary, emerging evidence indicates that miRNAs are actively involved in regulating gene expression patterns in the adult brain (Chandrasekar and Dreyer, 2011, Edbauer et al., 2010, Rajasethupathy et al., 2009, Smalheiser et al., 2010). Thus, we here focus on the role of miRNAs in neural plasticity and memory, as an important emerging component of the extraordinarily complex network of RNA regulation in brain function.