MicroRNAs and synaptic plasticity--a mutual relationship

Abstract

MicroRNAs (miRNAs) are rapidly emerging as central regulators of gene expression in the postnatal mammalian brain. Initial studies mostly focused on the function of specific miRNAs during the development of neuronal connectivity in culture, using classical gain- and loss-of-function approaches. More recently, first examples have documented important roles of miRNAs in plastic processes in intact neural circuits in the rodent brain related to higher cognitive abilities and neuropsychiatric disease. At the same time, evidence is accumulating that miRNA function itself is subjected to sophisticated control mechanisms engaged by the activity of neural circuits. In this review, we attempt to pay tribute to this mutual relationship between miRNAs and synaptic plasticity. In particular, in the first part, we summarize how neuronal activity influences each step in the lifetime of miRNAs, including the regulation of transcription, maturation, gene regulatory function and turnover in mammals. In the second part, we discuss recent examples of miRNA function in synaptic plasticity in rodent models and their implications for higher cognitive function and neurological disorders, with a special emphasis on epilepsy as a disorder of abnormal nerve cell activity.

Keywords: cognition; learning and memory; microRNA; neurological disease; neuronal activity; synaptic plasticity.

Figure 1.

Regulation of microRNA biogenesis by neuronal activity. (a) Activity-dependent miRNA transcription. Under basal conditions, the transcription of miRNA genes (blue) is under control of transcriptional activators (TA) or transcriptional repressors (TR) that bind to their respective regulatory sequences (left panel). Upon neuronal stimulation, specific TAs (e.g. CREB, Mef2) become active, resulting in an enhancement of pri-miRNA production (upper-right panel). This is accompanied also by histone modifications within the promoter region of activity-regulated miRNAs that favour transcription of miRNA genes (lower-right panel). (b) Most of the pri-miRNAs undergo the first enzymatic cleavage by the microprocessor complex, resulting in pre-miRNAs. This step can be regulated by RNA-binding proteins (RBP; left panel). It should be noted that post-translational modifications (PTMs, yellow circles) of Drosha and DGCR8 that facilitate pri-miRNA processing were only reported in non-neuronal cells so far, so the indicated regulation in neurons remain speculative (right panel). (c) After cytoplasmic export, pre-miRNAs undergo the second processing step by the Dicer–TRBP complex, resulting in the formation of miRNA duplexes. This step can be aided by RBPs such as FMRP (left panel). Upon neuronal stimulation, Dicer enzymatic activity increases following limited proteolysis or protein stabilization upon TRBP phosphorylation. In addition, activity-driven regulation of RBP protein levels (e.g. LIN28) can modulate the processing of specific pre-miRNAs in a bidirectional manner. (d) In the final steps of maturation, miRNA duplexes are unwound and the resulting single-stranded mature miRNAs are loaded in the RISC complex, which in turns targets complementary sequences within 3′UTRs of mRNAs. The RISC complex includes AGO2, GW182 and several auxiliary proteins (e.g. MOV10, FMRP), serves as platform for the recruitment of translational repressors (pale yellow) and possibly interferes with ribosomal function at different stages of translation (ribosome in grey). Upon neuronal activity, examples of both a reduction and enhancement of miRNA-mediated silencing have been described (see also figure 2).

Figure 2.

Dynamic regulation of microRNA function in neurons. Neuronal activity and other factors working in trans can influence miRNA-mediated repression bidirectionally. (a) Specific RBPs can compete with miRNAs for binding to target sites in the 3′UTRs in an activity-dependent manner, as shown for example for the HuD protein. (b) Activity-induced PTMs (yellow circles) of the RISC complex modulate the repressive function of miRNAs. For example, activity-dependent dephosphorylation of FMRP and proteasomal degradation of MOV10 lead to a release of RISC from target mRNAs. Examples of AGO2 PTMs induced by extracellular stimuli were only described in non-neuronal cells and therefore remain speculative in neurons. (c) Endogenous miRNA ‘sponges’, e.g. ciRS-7, are circular RNAs that contain several binding sites for miRNAs and are able to sequester the RISC away from other natural targets, thereby leading to a derepression. Whether circRNAs are subjected to activity-dependent regulation is unknown.