miRNAs in NMDA receptor-dependent synaptic plasticity and psychiatric disorders

Abstract

The identification and functional delineation of miRNAs (a class of small non-coding RNAs) have added a new layer of complexity to our understanding of the molecular mechanisms underlying synaptic plasticity. Genome-wide association studies in conjunction with investigations in cellular and animal models, moreover, provide evidence that miRNAs are involved in psychiatric disorders. In the present review, we examine the current knowledge about the roles played by miRNAs in NMDA (N-methyl-d-aspartate) receptor-dependent synaptic plasticity and psychiatric disorders.

INTRODUCTION

miRNAs are non-coding RNAs that fine-tune the expression of their target genes [1, 2]. More than 2500 miRNAs have been annotated in the human genome, and more than 60% of human protein-coding genes are predicted miRNA targets [3]. Hundreds of miRNAs are expressed specifically in mammalian brains and participate in a variety of functions, including cell differentiation, neural development, learning, memory and behaviour [4, 5]. In addition to globally modulating gene expression, miRNAs can be localized to synaptic sites where they are regulated by neuronal activity and influence synaptic function locally [6– 13]. In line with the importance of miRNAs for brains and synapses, miRNAs have been implicated in the aetiology and pathophysiology of neurodegenerative and psychiatric diseases [14–16]. For example, genetic variants in the MIR137 gene are associated with the risk of schizophrenia [14]. In the present review, we focus on recent progress in interrogating the functions of miRNAs in synaptic plasticity, especially NMDA (N-methyl-d-aspartate) receptor-dependent long-term synaptic potentiation and depression, and the genetic association of miRNAs with psychiatric disorders.

miRNA BIOGENESIS AND FUNCTION

miRNA biogenesis consists of three major steps, each of which produces a characteristic type of RNA (Figure 1). The first step is the transcription of miRNA genes by RNA polymerase II into pri-miRNAs (primary miRNAs), which usually are several kilobases long. The nuclear RNase III Drosha then recognizes the stem-loop structure of pri-miRNAs and cleaves them into pre-miRNAs (precursor miRNAs) which have 70–80 nt, a 2-nt 3′ overhang and a stem–loop structure [17]. Specific and effective cleavage of pri-miRNAs by Drosha requires DGCR8 (DiGeorge syndrome critical region 8), a double-stranded-RNA-binding protein that forms the pri-miRNA microprocessor complex with Drosha [18, 19]. Pre-miRNAs are transported from the nucleus to the cytoplasm by exportin-5 in a Ran/GTP-dependent manner [17]. The last step of miRNA biogenesis is the processing of pre-miRNAs by the RNase III Dicer, which recognizes the double-stranded region of the pre-miRNA hairpin and cleaves it into ~22 (15–34)-nt mature miRNAs [20, 21]. FMRP (fragile X mental retardation protein) interacts with miRNAs and Dicer [21].

Figure 1.

The biogenesis and regulation of miRNAs relevant to NMDA receptor-dependent synaptic plasticity

Mature miRNAs primarily function as post-transcriptional inhibitors of protein synthesis by inhibiting translation or destabilizing mRNAs. In some cell types or conditions, however, miRNAs can also promote translation [22, 23]. Translational inhibition by miRNAs occurs in RISC (mRNA-induced silencing complex) (Figure 1), a ribonuclear protein complex consisting of AGO (Argonaut) 1, AGO2, Pumilio 2, MOV10 (Moloney leukaemia virus 10) and FMRP [21, 24–26]. Mature miRNAs are loaded into RISC where they serve as a guide for recognizing target mRNAs through imperfect base pairing with the MRE (miRNA-response element) in the 3′-UTR, 5′-UTR or coding region of the mRNAs [27–32]. The binding of miRNAs and target mRNAs can induce mRNA deadenylation and recapping, thereby repressing translation [33–36].

SUBCELLULAR LOCALIZATION OF miRNAs IN NEURONS

Neurons have elaborative dendrites and axons which can extend a great distance from the soma. The maintenance and modulation of synapses, many of which located on distal neurites, are dependent on de novo protein synthesis [6]. Both mRNAs and the translational machinery are present in dendrites and axons, and local translation plays important roles in a variety of neuronal activities, including axon outgrowth, synaptic plasticity and dendritic spine remodelling [6–13]. In addition to regulating global translation, miRNAs also take part in local protein synthesis as implicated by the presence of a subset of pri-, pre-and mature miRNAs in dendrites, axons and synaptic fractions [6–13]. Proteins in the miRNA biogenesis pathway, such as Drosha, DGCR8 and Dicer, are also present in the PSD (postsynaptic density) fraction [37, 38]. Dicer in PSD is regulated by synaptic activity. NMDA stimulation of hippocampal slices or calcium treatment of synaptoneurosomes (a subcellular preparation enriched in pre- and post-synaptic components) causes the release of Dicer from PSD and enhancement of its RNase activity [37]. These observations suggest that miRNA production can be locally regulated by synaptic activity. This regulation serves as a post-transcriptional means of modulating protein synthesis in active synapses. This notion is supported by the findings that miRNAs (such as miR-26a, miR-191, miR-135 and miR-501-3p) are located in dendrites, and their expression can be regulated by synaptic activity [6, 7, 10–12, 38, 39]. For instance, NMDA receptor activation inhibits miR-191 expression locally in dendrites, which in turn leads to elevation of its target tropomodulin-2 [11].

miRNAs and RISC are also in axons [40]. Natera-Naranjo et al. [41] detected ~130 mature miRNAs in the axons of superior cervical ganglia neurons, and showed that several of them, including miR-16, miR-204, miR-221 and miR-15b, are highly enriched in distal axons. miR-338 is found in axons, where it regulates the translation of cytochrome c oxidase IV mRNAs [42]. In addition to mature miRNAs, a subset of pre-miRNAs, whose mature forms are enriched in the axons of sympathetic neurons, are also present in axons [43]. It is likely that the close proximity of miRNAs to synapses facilitates the spatial and temporal precision of synaptic protein regulation, thereby ensuring efficient and individualized modulation of synapses in response to synaptic excitation.

NMDA RECEPTOR-DEPENDENT SYNAPTIC PLASTICITY

The strength of synaptic transmission can be modulated by neural activity. Synaptic plasticity is the ability of synapses to increase or decrease their efficacies [44]. The change in synaptic strength can last from milliseconds to weeks [45]. Long-term synaptic plasticity, including LTP (long-term potentiation) and LTD (long-term depression) of synapses, is an important cellular mechanism underlying information storage in the brain [46–49]. Long-term synaptic plasticity can be classified by its primary site of expression (such as presynaptic plasticity and postsynaptic plasticity), or by the type of neurotransmitter receptor that is required for induction such as NMDA receptor-dependent, mGluR (metabotropic glutamate receptor)-dependent or muscarinic receptor-dependent plasticity [50–54]. The present review focuses on NMDA receptor-dependent LTP and LTD.

NMDA receptors are ionotropic glutamate receptors which are ubiquitously expressed in the nervous system. They are blocked by Mg²⁺ at resting membrane potentials and are activated by both glutamate binding and membrane depolarization (for the removal of Mg²⁺ blockade) [55]. A number of induction protocols are used to induce NMDA receptor-dependent synaptic plasticity, such as high-frequency (100 Hz) stimulation, theta burst stimulation, pairing of pre- and post-synaptic spiking, and low-frequency (1 Hz) stimulation [56–59]. In hippocampal slices, NMDA receptor activation results in Ca²⁺ influx which engages signalling cascades that regulate AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor trafficking [60]. The modulation of AMPA receptor trafficking results in insertion or removal of AMPA receptors from synapses, the primary mechanism underlying the expression of NMDA receptor-dependent synaptic plasticity [61–64]. The duration and exact mechanism of NMDA receptor-dependent synaptic plasticity are dependent on the stimulation intensity [63]. Strong stimulation induces long-lasting LTP or LTD that requires translation, whereas weak stimulation-induced synaptic modification persists for no more than 2 h and is independent of protein synthesis [64–67].

REGULATION OF NMDA RECEPTOR-DEPENDENT SYNAPTIC PLASTICITY BY miRNAs

miRNAs play multifaceted roles in NMDA receptor-dependent synaptic plasticity. They determine the capacity of neurons to modulate synaptic strength by controlling the expression level of NMDA receptors, AMPA receptors and signalling molecules in the synaptic plasticity pathway [43, 68–71]. They also modulate the translation of selective proteins in response to synaptic activation to maintain synaptic potentiation or depression for prolonged periods of time [72].

NMDA receptors are heterotetramers, containing two GluN1 subunits and two GluN2A–GluN2D or GluN3A/GluN3B sub-units [73]. The expression of GluN2A and GluN2B is developmentally regulated in the hippocampus, with GluN2A increasing and GluN2B decreasing during brain maturation [74]. NMDA receptors are miRNA targets [75, 76]. The 3′-UTRs of GluN2A and GluN2B mRNAs contain numerous computationally predicted miRNA-binding sites [71], and several of them have been experimentally validated. Corbel et al. [71] showed that GluN2B is targeted by miR-539 and GluN2A is targeted by miR-19a. Moreover, the same group showed that miR-539 and miR-19a are inversely correlated with GluN2B and GluN2A expression during development, and therefore appear to influence the temporal pattern of NMDA receptor expression [71]. Other researchers reported that the miR-223-binding site controls GluN2B expression in response to excitotoxicity [77], and the miR-125b–binding site in the GluN2A 3′-UTR confers the regulation by FMRP [78].

miRNAs also control the synaptic expression of AMPA receptors. Using the 3′-UTR of GluA1 mRNAs as bait, we pulled down their binding miRNAs and identified miR-501-3p as a regulator of GluA1 expression [12]. miR-501-3p not only determines the basal level of GluA1 expression, but also is responsible for NMDA receptor-dependent reduction in GluA1 in rat hippocampal neurons [12]. Moreover, miR-501-3p is up-regulated locally in dendrites following NMDA receptor activation, indicative of its contribution to local protein synthesis [12]. Other validated miRNAs targeting GluA1 mRNAs include miR-92a [79]. Letellier et al. [79] showed that miR-92 mediates the down-regulation of GluA1 in response to activity blockade by tetrodotoxin and AP5 (2R–amino-5-phosphonovaleric acid), a selective NMDA receptor antagonist [79]. The GluA2 subunit of AMPA receptors is regulated by miR-124, miR-223 and miR-181 [77, 80, 81].

Perturbation of miRNA biogenesis causes a global decrease in miRNA expression and an enhancement of synaptic plasticity. In the hippocampal CA1 region of heterozygous DGCR8-knockout mice, LTP is changed in an age-dependent manner, increasing in 16–20-week-old mice, but remaining intact in 8–10-week-old animals [82]. A 60 % loss of Dicer in adult mice has no effect on LTP, but increases post-tetanic potentiation [83]. Since most mRNAs can be targeted by many different miRNAs, and each miRNA regulates the translation of many different mRNAs that have the same MRE sequence [84], the global change in miRNA transcriptomes in DGCR8 and Dicer mutant mice hampers the extrapolation of each miRNA’s specific function. Individual miRNAs therefore need to be manipulated to address this issue.

Since it is a daunting task to investigate the synaptic functions of the hundreds of miRNAs expressed in mammalian brains one by one, several groups have used large-scale systematic approaches to identify candidate plasticity miRNAs. Park and Tang [85] induced chemical LTP with TEA (tetraethylammonium), a K⁺channel blocker, and mGluR-LTD in mouse hippocampal slices, and then extracted RNAs for miRNA microarray [85]. They detected 62 miRNAs in hippocampal slices [85]. With a few exceptions, the majority of them were up-regulated: 55 by LTP and 59 by mGluR-LTD induction [85]. The Bramham laboratory analysed miRNA expression using microarray in the rat dentate gyrus after in vivo LTP induction [86]. They showed that, of the 237 probes on the chip, ten miRNAs increased and 11 miRNAs decreased expression at 2 h after stimulation of the medial perforant pathway [86]. Using real-time PCR, they were able to validate the expression change in miR-132, miR-212 and miR-219, and detected alteration of mature and pri-miRNAs by NMDA receptor activation [86].

We recently combined the NGS (next-generation sequencing) platform and bioinformatic analysis to interrogate the functions of miRNAs in NMDA receptor-dependent LTP and LTD [11, 13]. The hippocampal slices were stimulated at the Schaffer collateral pathway with high-frequency stimulation for LTP induction or treated with NMDA for LTD induction. At 90 min after stimulation, the CA1 region was removed for RNA analysis with NGS. We detected a total of 438 miRNAs in the hippocampal CA1 area, with 70 of them changed in LTD (34 up-regulated and 36 down-regulated) and 12 changed in LTP (six down-regulated and six up-regulated) [11, 13]. It is interesting that all miRNAs up-regulated in LTP belong to the let-7 family [13]. We confirmed the NGS result using real-time PCR and tested the functional significance of miRNA expression change. We found that the alteration of miR-26a and miR-384-5p is required for protein-synthesis-dependent maintenance, but not induction, of LTP [13]. We identified RSK3 (ribosomal S6 kinase 3),a protein kinase that regulates translation, as a target gene that mediates the functions of miR-26a and miR-384-5p in LTP [13].

Of the miRNAs changed in LTD, we selected miR-191 and miR-135 for functional analysis and revealed that they are required for LTD induction [11]. In addition, both miR-191 and miR-135 are required for maintenance, but not induction, of spine remodelling accompanying LTD [11]. The reduction in miR-191 in LTD leads to an increase in tropomodulin-2 (an actin cytoskeleton regulator), whereas complexin-1/2, which regulates AMPA receptor exocytosis, confers the function of miR-135 in spine remodelling [11].

We examined the concerted effect of the miRNA transcriptome change on gene expression and cellular activities using bioinformatics. This approach shows that the target genes of miRNAs altered in LTP or LTD are enriched in cellular pathways related to synaptic functions and dendritic spines, such as ‘synaptic transmission’, ‘actin filament-based process’, ‘cytoskeletal protein binding’, ‘regulation of phosphorylation’, and ‘small GTPase-mediated signal transduction’ [11, 13]. These miRNAs therefore function as hubs that orchestrate the structural and functional modification of synapses.

The changes in miRNAs following NMDA receptor activation vary in direction and magnitude, indicative of the heterogeneity of the underlying induction mechanisms. NMDA receptor activity is both necessary and sufficient to alter miRNA expression, whereas GluN2A–containing and GluN2B–containing NMDA receptors play different roles [87]. In LTD, GluN2A activity is required for the increases in miR-135 and miR-501-3p [11, 12], whereas the decrease in miR-191 is caused by GluN2B activation [11]. Both transcriptional and post-transcriptional regulation of miRNAs is engaged in by GluN2A and GluN2B in LTD. By contrast, GluN2A is responsible for the decreases in miR-26a and miR-384-5p at post-transcriptional levels in LTP [13]. It remains to be determined, however, how GluN2A and GluN2B control miRNA expression. In the rat dentate gyrus, miR-132 and miR-212 increase following LTP induction by high-frequency stimulation of the medial perforant pathway. This increase requires transcription and is abolished by the group 1 mGluR antagonist AIDA [(RS)-1-aminoindan-1,5-dicarboxylic acid]. AIDA does not affect LTP induction or maintenance, but blocks activity-dependent depotentiation of LTP. miRNAs that are related to NMDA receptor-dependent synaptic plasticity are listed in Table 1, and the regulation of their expression is illustrated in Figure 1.

Table 1.

miRNAs relevant to NMDA receptor-dependent synaptic plasticity

miRNA	Links to NMDA receptor-dependent synaptic plasticity	Reference(s)
miR-19a	Regulates GluN2A expression	[71]
miR-26a	Down-regulated by GluN2A–dependent mechanisms in LTP, required for protein synthesis-dependent maintenance (but not induction) of LTP	[13]
miR-34a	Decreases the density of NMDA-evoked currents and facilitates synaptic response	[72]
miR-92a	Mediates tetrodotoxin and AP5-induced down-regulation of GluA1	[79]
miR-124	Controls GluA2 surface expression	[80]
miR-125b	Targets GluN2A, increases longer and thinner dendritic protrusions, and weakens synaptic strength	[78]
miR-132	Down-regulated by NMDA receptor activation, up-regulated by BDNF (brain-derived neurotrophic factor), mediates BDNF-induced increases in GluN2A and GluN2B, increases the width of dendritic protrusions, and enhances synaptic strength	[78, 86, 113]
miR-135	Required for maintenance of spine restructuring in NMDA receptor-dependent LTD by regulating AMPA receptor exocytosis	[11]
miR-181	Enriched at medium spiny neuron synapses of the nucleus accumbens, induced by dopamine signalling in primary neurons, reduces GluA2 surface expression, spine formation and mEPSC (miniature excitatory postsynaptic current) frequency in hippocampal neurons	[81]
miR-191	Required for maintenance of spine restructuring in NMDA receptor-dependent LTD by regulating actin depolymerization	[11]
miR-212	Down-regulated by NMDA receptor activation	[86]
miR-219	Down-regulated by NMDA receptor activation, inhibits NMDA receptor function by targeting CaMKIIγ (Ca2+/calmodulin-dependent protein kinase IIγ)	[86, 114]
miR-223	Reduces GluN2B and inhibits NMDA-induced Ca2+ influx	[77]
miR-384-5p	Down-regulated by GluN2A–dependent mechanisms in LTP, required for protein synthesis-dependent maintenance (but not induction) of LTP	[13]
miR-501-3p	Up-regulated locally in dendrites by GluN2A activation, and this increase is required for NMDA-induced suppression of GluA1 expression and long-lasting remodelling of dendritic spines	[12]
miR-539	Regulates GluN2B expression	[71]

In addition to NMDA receptor-dependent synaptic plasticity, miRNAs participate in other forms of synaptic plasticity. miR-124 inhibits serotonin-induced synaptic facilitation by regulating CREB (cAMP-response-element-binding protein), a transcription factor, in Aplysia [8], miR-92 contributes to tetrodotoxin and AP5-induced homoeostatic synaptic scaling by controlling GluA1 expression [79], overexpression of miR-132 increases the paired-pulse ratio (a form of short-term presynaptic plasticity) [88], knockout of miR-132 and miR-212 enhances in the hippocampus (but inhibits in the cortex) theta burst-induced LTP [89], and miR-137 overexpression impairs mossy fibre LTP [90].

miRNA GENES IN THE AETIOLOGY OF PSYCHIATRIC DISORDERS

The structure, function and plasticity of synapses are pivotal for normal brain function, and their impairments are closely associated with brain disorders. Along with the findings of diverse and important functions influenced by miRNAs in synaptic physiology, human genetic studies indicate that miRNAs are associated with a risk of psychiatric disorders, including schizophrenia, ASD (autism spectrum disorder), bipolar disorder and panic disorder.

Analysis of CNVs (copy number variants), a form of rare structural genetic changes, reveals that people carrying the 22q11.2 deletion have an increased risk of mental illness such as schizophrenia [91, 92]. The 22q11.2 locus contains seven miRNA genes and DGCR8 [19, 93]. DGCR8 haploinsufficiency causes miRNA deficiency and contributes to synaptic alterations found in the 22q11.2-deletion mouse model [94]. Moreover, a genome-wide survey of miRNAs in rare CNVs shows that the schizophrenia group is enriched in individuals with a rare CNV overlapping a miRNA gene [95].

GWAS (genome-wide association studies) also point out the contribution of miRNAs to the genetic basis of schizophrenia. The Psychiatric Genomics Consortium recently reported a GWAS using 36989 cases and 113075 controls, and identified 108 genomic loci that are associated with schizophrenia [96]. It was noted that the 108 loci contain 22 miRNA genes [96–98]. In a schizophrenia GWAS of >21856 individuals of European ancestry and a replication sample of 29839 independent subjects, the strongest genome-wide significant association identified is within the MIR137 gene [99]. The association of MIR137 with schizophrenia is corroborated by a later GWAS in a Swedish national sample (5001 cases, 6243 controls) that reported 22 genome-wide significant regions, one of which is the MIR137 locus [100]. miR-137 regulates presynaptic plasticity in human neurons [90]. In neurons differentiated from human fibroblasts, the minor allele SNPs (single nucleotide polymorphisms) associated with schizophrenia at the MIR137 locus cause an increase in miR-137 expression, down-regulation of its presynaptic target genes (complexin-1, Nsf and synaptotagmin-1), and impairment of vesicle release, mossy fibre LTP and hippocampus-dependent learning and memory [90]. miR-137 may therefore contribute to the synaptopathology of schizophrenia. The genetic association of genes with schizophrenia implies that gene expression is altered in schizophrenia. Indeed, hundreds of genes are found to be altered in various brain regions of schizophrenics. These findings, however, are difficult to interpret, because almost all patients have been treated with antipsychotics, which probably affect gene expression in the brain. Giving this confounding factor and the comprehensive reviews in the literature on gene expression changes in schizophrenia [101–105], we focus the present review on genetic studies [102].

In addition to schizophrenia, miRNA genes are associated with other psychiatric disorders. The 22q11.2 deletion is also associated with ASDs [106]. The ASD-associated 3p14.1, 7q11.23 and 10q11.23-21.1 loci contain a total of four miRNA genes [107–109]. A gene-based analysis of all known autosomal miRNAs using a GWAS dataset of bipolar disorder (9747 patients and 14278 controls) found nine miRNAs that showed significant associations with bipolar disorder [110]. miRNAs are potentially involved in the aetiology of panic disorder [111]. A case–control study for SNPs tagging miRNA genes in patients with panic disorder showed that several miRNA genes are associated with the disease [112]. miRNAs that are genetically associated with psychiatric disorders are listed in Table 2.

Table 2.

miRNAs implicated in psychiatric disorders by GWAS and CNV studies

miRNA	Disease	Reference(s)
miR-499, miR-708, miR-1908	Bipolar disorder	[110]
miR-23a-5p, miR-29b2, miR-29c, miR-30e, miR-130a, miR-137, miR-146b-3p, miR-185, miR-211, miR-548AJ2, miR-648, miR-649, miR-650, miR-767-5p, miR-1228, miR-1281, miR-1286, miR-1306, miR-1307, miR-2682, miR-3160-1, miR-3160-2, miR-3618, miR-3655, miR-3667-3P, miR-3667-5p, miR-4301, miR-4304, miR-4529, miR-4677, miR-4761, miR-4771, miR-6773, miR-6816, miR-6889, miR-8064, miR-8072	Schizophrenia	[95–98, 115–120]
miR-34a, miR-124, miR-181b, miR-195, miR-200b, miR-211, miR-429, miR-486, miR-497, miR-548f, miR-570, miR-590-3p, miR-605, miR-630, miR-944, miR-1286, miR-1306, miR-3136, miR-3618, miR-4284, miR-4715	Autism spectrum disorders	[108, 109, 121–125]
miR-22, miR-138-2, miR-148a, miR-488, miR-491	Panic disorders	[111]

CONCLUSIONS AND PERSPECTIVES

The experimental evidence discussed above indicates that miRNAs play both permissive and instructive roles in the modulation of NMDA receptor-dependent synaptic plasticity. They set the basal levels of synaptic proteins to enable the induction and expression of synaptic plasticity, and reset their expression in response to NMDA receptor activation to engage the signalling cascades for long-term modification of synapses. Although in both LTP and LTD, miRNAs are changed in a NMDA receptor-dependent manner, the isoform of NMDA receptors and the specific miRNAs that are involved differ. Hence the mechanisms underlying neuronal activity-dependent miRNA expression appear to vary by specific miRNAs. The mechanistic link between NMDA receptor activation and miRNA expression, however, is currently unknown. It is an interesting question for future research.

Only a few of the hundreds of brain-expressed miRNAs have been examined for their functions. Given that a large number of miRNAs target to synaptic proteins or signalling proteins regulating synapses, it is predicted that more miRNAs function in synaptic plasticity. Laborious experimental testing is a major limiting step in characterizing individual miRNAs. High-throughput functional tests are needed to facilitate this process.

The implication of synaptic plasticity in cognition and the genetic association of miRNAs with psychiatric disorders raise the possibility that miRNAs contribute to the pathogenesis of psychiatric disorders, in part, through their influence on synaptic plasticity. This notion is supported by the findings that some miRNAs (such as miR-137) conferring risk of psychiatric diseases regulate synaptic plasticity in rodents. However, it needs to be consolidated by more experiments testing the significance of synaptic plasticity for psychiatric disorders and functions of risk miRNAs.

Abbreviations

AGO

Argonaut

AIDA

(RS)-1-aminoindan-1,5-dicarboxylic acid

AMPA

α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid

AP5

2R–amino-5-phosphonovaleric acid

ASD

autism spectrum disorder

CNV

copy number variant

DGCR8

DiGeorge syndrome critical region 8

FMRP

fragile X mental retardation protein

GWAS

genome-wide association studies

LTD

long-term depression

LTP

long-term potentiation

mGluR

metabotropic glutamate receptor

MRE

miRNA-response element

NGS

next-generation sequencing

NMDA

N-methyl-d-aspartate

pre-miRNA

precursor miRNA

pri-miRNA

primary miRNA

PSD

postsynaptic density

RISC

mRNA-induced silencing complex

SNP

single nucleotide polymorphism