Synaptic adaptations by alcohol and drugs of abuse: changes in microRNA expression and mRNA regulation

Abstract

Local translation of mRNAs is a mechanism by which cells can rapidly remodel synaptic structure and function. There is ample evidence for a role of synaptic translation in the neuroadaptations resulting from chronic drug use and abuse. Persistent and coordinated changes of many mRNAs, globally and locally, may have a causal role in complex disorders such as addiction. In this review we examine the evidence that translational regulation by microRNAs drives synaptic remodeling and mRNA expression, which may regulate the transition from recreational to compulsive drug use. microRNAs are small, non-coding RNAs that control the translation of mRNAs in the cell and within spatially restricted sites such as the synapse. microRNAs typically repress the translation of mRNAs into protein by binding to the 3'UTR of their targets. As 'master regulators' of many mRNAs, changes in microRNAs could account for the systemic alterations in mRNA and protein expression observed with drug abuse and dependence. Recent studies indicate that manipulation of microRNAs affects addiction-related behaviors such as the rewarding properties of cocaine, cocaine-seeking behavior, and self-administration rates of alcohol. There is limited evidence, however, regarding how synaptic microRNAs control local mRNA translation during chronic drug exposure and how this contributes to the development of dependence. Here, we discuss research supporting microRNA regulation of local mRNA translation and how drugs of abuse may target this process. The ability of synaptic microRNAs to rapidly regulate mRNAs provides a discrete, localized system that could potentially be used as diagnostic and treatment tools for alcohol and other addiction disorders.

Keywords: cocaine; ethanol; mRNA targets; miRNAs; stimulants; synaptic translation; synaptoneurosomes.

FIGURE 1

Alcohol affects local translation of proteins in amygdala of alcohol-dependent rats. Alcohol exposure using conditioning chambers, as well as a non-pharmacologically active alcohol injection (priming) that served as an odor-taste cue, increased mTORC1 (mammalian target of rapamycin complex 1) activation and the phosphorylation/activation of its downstream substrates, such as eukaryotic translation initiation factor-4E binding protein (4E-BP), S6 kinase (S6K) and the S6K substrates, and increased expression of post-synaptic density-95 (PSD95) and the AMPA receptor GluA1 subunit (Barak et al., 2013). These effects were abolished by the mTORC1 inhibitor, rapamycin. A second pathway by which alcohol mediates synaptic translation is by increasing extracellular glutamate. This leads to activation of voltage-dependent Ca²⁺ channels (VDCCs) and activity-dependent release of brain-derived neurotrophic factor (BDNF). BDNF then binds and stimulates its receptor, tropomyosin-related kinase B (TrkB), activating downstream signaling pathways, including phosphatidyl inositol-3 kinase (PI3K), Akt and Ras, stimulating mTORC1, which culminates in the signaling effects described above. The increased GluA1-subunits are inserted into the membrane, increasing excitation and alcohol-sensitive substrates. Thus, mTORC1 activation mediates the translation of specific synaptic proteins that are important in plasticity processes. Figure and legend were adapted from Duman and Voleti (2012). Abbreviations: 4E-BP, 4E binding protein; eEF2K, eukaryotic elongation factor-2 kinase; ERK, extracellular signal-regulated kinase; MEK, MAP/ERK kinase; P indicates phosphorylated protein.

FIGURE 2

Model for cocaine-induced microRNA-mRNA interactions. Cocaine causes the down-regulation of let-7d, resulting in induction of its target genes, BDNF and cAMP-responsive element-binding protein (CREB). In contrast, miR-181a is up-regulated by cocaine, causing down-regulation of its targets, GRM5 (glutamate metabotropic receptor 5) and AMPA receptor subunit 2 (GluA2). These data support the involvement of let-7d and miR-181a in regulating the differential expression of various genes in response to cocaine, which may impact molecular adaptations leading to addiction. Figure and legend were modified from the original in Jonkman and Kenny (2013).

FIGURE 3

The interactions between miR-212, CREB, methyl CpG-binding protein 2 (MeCP2), and BDNF. Cocaine activates CREB-miR-212 and MeCP2-BDNF signaling and the balance between these pathways likely regulates escalation of cocaine intake (‘loss of control’). The orange circle illustrates CREB signaling, which protects against the development of escalating cocaine intake, whereas the green circle shows that MeCP2-BDNF signaling promotes escalation of intake. Green arrows indicate a stimulatory relationship, whereas red lines indicate an inhibitory relationship. Figure and legend were taken from Jonkman and Kenny (2013).