Glutamate-mediated excitotoxicity is the major neuropathological process contributing to numerous neurological diseases. Recently, emerging evidence indicates that microRNAs (miRNAs) play essential roles in the pathophysiology of a wide range of neurological diseases. Notably, there have been significant developments in understanding the biogenesis of miRNAs, their regulatory mechanisms, and their potential as effective biomarkers and therapies. In the present review, we summarize the recent literature that highlights the versatile roles played by miRNAs in glutamate receptor (GluR)-dependent neurological diseases. Based on the reported studies to date, modulation of miRNAs could emerge as a promising therapeutic target for a variety of neurological diseases that were discussed in this review.

Introduction

Glutamate receptors (GluRs) are the predominant excitatory neurotransmitter receptors that regulate a broad spectrum of physiological and pathological processes in the brain [1]. It is well established that glutamate excitotoxicity plays critical roles in many types of acute and chronic central nervous system (CNS) diseases and injuries. Nevertheless, many types of anti-glutamate receptor antibodies can undoubtedly do so too by inducing several pathological effects in the CNS [2]. Under normal conditions, glutamate signaling activates the ionotropic and metabotropic GluRs that leads to stimulation of neurons and glial cells. However, dysregulation and pathological signaling of glutamate receptors are involved in a number of neurological diseases [3,4].

MicroRNAs (miRNAs) are short noncoding RNAs that act as posttranscriptional repressors by binding to the 3′-untranslated region (3′-UTR) of target messenger RNA (mRNA) transcripts. Accumulating evidence strongly suggests that the expression of miRNAs change in relation to various neurological disorders such as epilepsy, stroke, multiple sclerosis (MS), and Alzheimer’s disease (AD) [58]. In recent years, researchers have found a link between miRNAs and glutamate receptors-mediated neurological diseases [9,10]. Although increasing evidence indicates that trafficking and phosphorylation of receptors have a major role in glutamate receptor’s regulation in CNS, the underlying mechanisms behind still incompletely understood.

In the present review, we focus on recent progress in interrogating the functions of miRNAs in glutamate receptor-dependent neurological diseases.

Biogenesis of miRNAs

miRNA biogenesis is a multistep process facilitated by several enzymes. Briefly, miRNAs transcription begins in the nucleus from either their intergenic region or intronic region of the hosting gene (Figure 1). Large numbers of miRNAs are transcribed mainly by RNA polymerase II (Pol-II) that synthesizes hairpin structures called primary miRNA (pri-miRNAs) [11]. The released pri-miRNAs are then processed by a series of nuclear enzymes cleavage with the aids of endoribonuclease Drosha and DiGeorge syndrome critical region 8 (DGCR8) to generate a stem–loop called precursor miRNA (pre-miRNA) [12]. Subsequently, pre-miRNA is exported into the cytoplasm through exportin-5 to form a duplex RNA of ∼22 nt with the aid of the RNase III enzyme Dicer [13]. The guide strand (miRNA) of the duplex, in most cases, is embedded onto Argonaute (AGO) proteins to produce the RNA-induced silencing complex (RISC), whereas the passenger strand (miRNA*) is degraded from AGO [14]. Mature miRNAs primarily function as posttranscriptional inhibitors of protein synthesis by either degradation of the mRNA or translational repression. In some cell types or conditions, however, miRNAs can also promote translation [15].

miRNA biogenesis and mode of action

Figure 1
miRNA biogenesis and mode of action

In the nucleus miRNA is transcribed to release a pri-miRNA which is cleaved to form a pre-miRNA which is exported into the cytoplasm through Exportin-5. In the cytoplasm a miRNA duplex is produced and the strand designated to be the mature sequence is loaded onto AGO preiiens producing RISC to modulate the translation of its target mRNA.

Figure 1
miRNA biogenesis and mode of action

In the nucleus miRNA is transcribed to release a pri-miRNA which is cleaved to form a pre-miRNA which is exported into the cytoplasm through Exportin-5. In the cytoplasm a miRNA duplex is produced and the strand designated to be the mature sequence is loaded onto AGO preiiens producing RISC to modulate the translation of its target mRNA.

miRNAs in glutamate receptors

GluRs are divided into two families: ionotropic (iGluR) and metabotropic (mGluR) [16,17]. Further, the iGluR family includes the N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate receptor subfamilies whereas mGluRs are further categorized into the group I, II, and III subfamilies [18]. A considerable amount of research has been devoted to miRNAs dysregulation involved in alteration of glutamate receptors. Evidence shows that miRNAs play multifaceted roles in NMDA receptor-dependent synaptic plasticity. Table 1 provides a summary of miRNAs and their possible targets in relation to glutamate receptors.

Table 1

Summary of miRNAs and their possible targets in relation to glutamate receptors

miRLinks to glutamate receptorReferences
132 Reduced by 1mGluR inhibition, reduced by NMDA receptor stimulation, mediates brain-derived neurotrophic factor (BDNF)-induced increases in GluN2A and GluN2B, up-regulates GluN2A, GluN2B, and GluR1 expression [21,61,6
124 Regulates GluA2 surface expression , up-regulates glutamate transporter-1 (GLT-1) [33,35
204 GluN1 [104
181a Down-regulates GluA2, up-regulates GLT-1 [32,36,37
21 Induced by prolonged NMDA receptor stimulation [28
212 Reduced by NMDAR stimulation [21
92a Mediates tetrodotoxin and AP5-induced down-regulation of GluA1 [29
284  Up-regulates GluRIIA and GluRIIB expression [38
1000 Down-regulates vesicular glutamate transporter (VGlut) [42
19a Down-regulates GluN2A expression [23
26a Down-regulated by GluN2A-dependent mechanisms in long-term potentiation (LTP) )[27
34a Decreases the density of NMDA-evoked currents [22
135 Required for maintenance of spine restructuring in NMDA receptor-dependent long-term depression (LTD) by controlling AMPA receptor exocytosis [25
191 Required for maintenance of spine restructuring in NMDA receptor-dependent LTD by regulating actin depolymerization [25
219 Down-regulated by NMDAR stimulation [21
384-5p Down-regulated by GluN2A-dependent mechanisms in LTP [27
501-3p Increased by GluN2A stimulation, and this up-regulation is required for NMDA-induced suppression of GluA1 expression [26
539 Controls GluN2B expression [23
153 Regulates GluA1 expression [30
137 Controls GluA1 expression, induced by mGluR5 stimulation [31
23a-3p Up-regulated after LTP, regulated NMDAR [39,41
151-3p Up-regulated after LTP, regulate NMDAR [39,41
miRLinks to glutamate receptorReferences
132 Reduced by 1mGluR inhibition, reduced by NMDA receptor stimulation, mediates brain-derived neurotrophic factor (BDNF)-induced increases in GluN2A and GluN2B, up-regulates GluN2A, GluN2B, and GluR1 expression [21,61,6
124 Regulates GluA2 surface expression , up-regulates glutamate transporter-1 (GLT-1) [33,35
204 GluN1 [104
181a Down-regulates GluA2, up-regulates GLT-1 [32,36,37
21 Induced by prolonged NMDA receptor stimulation [28
212 Reduced by NMDAR stimulation [21
92a Mediates tetrodotoxin and AP5-induced down-regulation of GluA1 [29
284  Up-regulates GluRIIA and GluRIIB expression [38
1000 Down-regulates vesicular glutamate transporter (VGlut) [42
19a Down-regulates GluN2A expression [23
26a Down-regulated by GluN2A-dependent mechanisms in long-term potentiation (LTP) )[27
34a Decreases the density of NMDA-evoked currents [22
135 Required for maintenance of spine restructuring in NMDA receptor-dependent long-term depression (LTD) by controlling AMPA receptor exocytosis [25
191 Required for maintenance of spine restructuring in NMDA receptor-dependent LTD by regulating actin depolymerization [25
219 Down-regulated by NMDAR stimulation [21
384-5p Down-regulated by GluN2A-dependent mechanisms in LTP [27
501-3p Increased by GluN2A stimulation, and this up-regulation is required for NMDA-induced suppression of GluA1 expression [26
539 Controls GluN2B expression [23
153 Regulates GluA1 expression [30
137 Controls GluA1 expression, induced by mGluR5 stimulation [31
23a-3p Up-regulated after LTP, regulated NMDAR [39,41
151-3p Up-regulated after LTP, regulate NMDAR [39,41

miR-219 expression not only is decreased by NMDA receptor activation, but also can suppress NMDA receptor function via regulating Ca2+/calmodulin-dependent protein kinase IIγ (CaMKIIγ), a component of the NMDAR signaling cascade [1921]. This bidirectional interaction was first noticed in prefrontal cortex (PFC) of mice with neurobehavioral dysfunction [19]. Recent studies have evaluated the significance of local changes in miR-219 and NMDAR expression levels during LTP and epilepsy [20,21]. miR-34a is implicated in cell proliferation, morphology, and function of developing neurons that improve behavioral functions by inhibiting the density of NMDA-evoked currents [22]. Other studies have precisely investigated the link between synaptic expression of NMDA subunits and miRNAs levels. Corbel et al. [23] reported that GluN2B is the target of miR-539 that also has the ability to modify a regulator of NMDAR subunit expression called repressor element 1 silencing transcription factor (REST). They also observed that miR-19a is inversely correlated with its target, GluN2A, during development. Other validated miRNAs targeting GluN2A include miR-125b. Studies also suggest that GluN2A is the direct target of this miR-125b in hippocampal neurons and its overexpression or knockdown results in GluN2A up- and down-regulation respectively [24]. Other researchers found that the miR-223-binding site controls GluN2B expression in response to excitotoxicity [9], and the miR-125b-binding site in the GluN2A 3′-UTR confers the regulation by fragile X mental retardation protein (FMRP) [24]. In LTD, GluN2A activity is required for the increases in miR-135 and miR-501-3p [25,26], whereas the decrease in miR-191 is caused by GluN2B activation [25]. Besides, it was also observed that GluN2A is responsible for the decreases in miR-26a and miR-384-5p at posttranscriptional levels in LTP [27]. However, it is still unclear how GluN2A and GluN2B regulate miRNA expression. NMDA receptor activation was found to up-regulate miR-21 in neurons suggesting that miRNAs and glutamate receptors can be bidirectionally interacted [28].

miRNAs were also found to regulate the synaptic expression of AMPA receptors. Several miRNAs have been suggested to target the GluA1 (also known as GluR1) subunit of AMPA receptors including miR-501-3p, miR-92a, miR-153, miR-137, and miR-183. Hu et al. [26] reported that miR-501-3p not only regulates the basal level of GluA1 expression, but also is responsible for NMDA receptor-dependent reduction in GluA1 in rat hippocampal neurons. Moreover, miR-501-3p is increased locally in dendrites by GluN2A activation, indicative of its contribution to local protein synthesis. Letellier et al. [29] showed that miR-92 mediates the decrease of GluA1 in response to activity blockade by tetrodotoxin and 2R-amino-5-phosphonovaleric acid (AP5), a selective NMDA receptor antagonist. Mathew et al. [30] identified miR-153 as a negative regulator of synaptic plasticity by targeting GluA1. Besides, it is also observed that knockdown of miR-153 enhanced fear memory in mice. Loohuis et al. showed that miR-137-binding site controls GluA1 expression and its knockdown selectively increases AMPAR-mediated synaptic transmission and activates synapses [31]. In contrast, its overexpression selectively decreases AMPAR-mediated synaptic transmission and deactivate synapses. Furthermore, miR-137 was transiently increased in response to mGluR5, but not mGluR1 activation [31].

The GluA2 (also known as GluR2) subunit of AMPA receptors is targeted by miR-183, miR-124, miR-223, and miR-181 [9,32,33]. In a recent study by Xie et al. [34], overexpression of miR-183 was found to inhibit AMPA receptors GluA1 and GluA2 by suppressing mammalian target of rapamycin (mTOR)/vascular endothelial growth factor (VEGF) pathway which in turn can significantly relieve neuropathic pain in chronic compress injury model. A recent study reported that the distribution and regulation of GluA2 can be regulated by miR-124 [33]. Evidence also shows that neuronal exosomal miR-124 can control astroglial GLT-1 (also known as SLC1A2 or EAAT2) expression in astrocytes [35]. Other studies have shown that GluA2 and GLT-1 are regulated by miR-181a [32,36,37]. Karr et al. [38] identified miR-284 as a regulator of glutamate receptor IIA (GluRIIA) and GluRIIB expression in Drosophila neuromuscular junctions. miR-284 knockdown was found to up-regulate the expression of GluRIIA and GluRIIB proportional to the number of predicted binding sites in each transcript.

Ryan et al. [39] found that miR-23a-3p and miR-151-3p expressions are increased after LTP induction, which is known to be expressed in adult rat synapses [40]. The same group performed bioinformatics analysis of LTP-related gene networks and predicted that the ongoing and dynamic transcriptional response to LTP induction contributes to alteration of synapses, glutamate receptors, and synaptogenesis [41]. Therefore, more studies are needed to explore whether the regulation of these miRNAs is dependent on NMDA receptor activation.

Recent evidence increasingly supports a role for miRNA in response to mGluRs alterations. As reported by previous research, in the rat dentate gyrus, miR-132 and miR-212 increase following LTP induction by stimulation of the medial perforant pathway. This increase requires transcription and is depleted by mGluR1 antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA) [21]. miR-1000 was demonstrated to presynaptically target the VGlut by an activity-dependent fashion. It has also been shown that genetically knocked down miR-1000 results in glutamate excitotoxicity and early-onset neuronal damage and death [42].

miRNAs in glutamate receptor-dependent neurological diseases

Research of miRNA involvement in glutamate-dependent neurological diseases is still at its early stage. Although there are multiple miRNAs involved in glutamate receptors, most of them currently do not have a clear function in relation to neurological diseases (Table 1). Over the past few decades, there have been major advances in our understanding of the role of glutamate receptors in a variety of neurological disorders, including epilepsy [43], stroke [44,45], AD [4648], MS [49], and neuropathic pain (Figure 2) [50]. Recent studies have shown the significance of miRNAs, and have suggested a potential role for specific miRNAs in the underlying pathophysiology of glutamate-mediated diseases. In particular, NMDA receptors have been the focus of intense study from both a physiological and a pharmacological perspective. In the following, we will summarize the evidence for roles of miRNAs in glutamate-dependent neurological diseases (Table 2).

miRNAs involved in GluR-dependent neurological diseases

Figure 2
miRNAs involved in GluR-dependent neurological diseases

miRNAs are critical regulators of various neurological diseases by modulating the abundance and availability of GluRs.

Figure 2
miRNAs involved in GluR-dependent neurological diseases

miRNAs are critical regulators of various neurological diseases by modulating the abundance and availability of GluRs.

Table 2

Summary of miRNAs involved in glutamate receptor-dependent neurological diseases

miRNeurological diseaseTargetCorrelationReferences
139-5p Temporal lobe epilepsy (TLE) GluN2A Negative correlation [10
219 Epilepsy GluN1 and CaMKIIγ Negative correlation [20
124 Epilepsy NMDAR Negative correlation [52
204 Mesial temporal lobe epilepsy (mTLE) GRM1 Negative correlation [53
218 mTLE GRM1, GLT-1 Negative correlation [53
219 Cerebral ischemia GluN1 Negative correlation [58
223 Cerebral ischemia GluN2B, GluA2 Negative correlation [9
132 Cerebral ischemia NMDAR Negative correlation [60
107 Cerebral ischemia GLT-1 Negative correlation [63
142-3p MS GLAST Negative correlation [71
124 MS AMPAR Negative correlation [72
Let-7b Anti-NMDAR encephalitis NMDAR Positive correlation [73
34a AD GRM7 Negative correlation [98
137 Cognitive impairments GluA1 Negative correlation [31
335 Major depressive disorder (MDD) Glutamate receptor 4 (GRM4) Negative correlation [82
1202 MDD GRM4 Negative correlation [80,81
101b MDD SLC1A1 Negative correlation [83
137 Poststroke depression GluN2A Negative correlation [87
219 Schizophrenia (SCZ) GluN2B Positive correlation [94
132 SCZ NMDAR Positive correlation [92
107 SCZ GluN3A Negative correlation [96
219 Neurobehavioral dysfunction NMDAR, CaMKIIγ Positive correlation [19
125b Fragile X syndrome (FXS) GluN2A Positive correlation [24
183 Neuropathic pain GluA1 and GluA2 Negative correlation [34
miRNeurological diseaseTargetCorrelationReferences
139-5p Temporal lobe epilepsy (TLE) GluN2A Negative correlation [10
219 Epilepsy GluN1 and CaMKIIγ Negative correlation [20
124 Epilepsy NMDAR Negative correlation [52
204 Mesial temporal lobe epilepsy (mTLE) GRM1 Negative correlation [53
218 mTLE GRM1, GLT-1 Negative correlation [53
219 Cerebral ischemia GluN1 Negative correlation [58
223 Cerebral ischemia GluN2B, GluA2 Negative correlation [9
132 Cerebral ischemia NMDAR Negative correlation [60
107 Cerebral ischemia GLT-1 Negative correlation [63
142-3p MS GLAST Negative correlation [71
124 MS AMPAR Negative correlation [72
Let-7b Anti-NMDAR encephalitis NMDAR Positive correlation [73
34a AD GRM7 Negative correlation [98
137 Cognitive impairments GluA1 Negative correlation [31
335 Major depressive disorder (MDD) Glutamate receptor 4 (GRM4) Negative correlation [82
1202 MDD GRM4 Negative correlation [80,81
101b MDD SLC1A1 Negative correlation [83
137 Poststroke depression GluN2A Negative correlation [87
219 Schizophrenia (SCZ) GluN2B Positive correlation [94
132 SCZ NMDAR Positive correlation [92
107 SCZ GluN3A Negative correlation [96
219 Neurobehavioral dysfunction NMDAR, CaMKIIγ Positive correlation [19
125b Fragile X syndrome (FXS) GluN2A Positive correlation [24
183 Neuropathic pain GluA1 and GluA2 Negative correlation [34

Epilepsy

Epilepsy is a chronic neurological disorder that is characterized by recurrent unprovoked seizures. Regardless of its underlying etiologies, an epileptic seizure reflects an abnormal balance between inhibition and excitation that leads to abnormal hypersynchronous electrical activity of neuronal networks [51]. Previous studies have provided evidence for the critical role of alterations in distribution of neurotransmitter receptor subtypes in neuronal hyperexcitability during epilepsy [43]. Several miRNAs found to be dysregulated in epilepsy. Among these miRNAs, miR-124, miR-139-5p, and miR-219 are of increasing importance in NMDA receptor-dependent epilepsy [10,20,52]. These miRNAs were studied in depth due to their specificity and/or enrichment in the brain.

In a recent study by Wang et al. [52], intrahippocampal administration of a brain-specific miR-124 duplex was associated with the suppression of seizure severity and prolongation of onset latency in rat models of epilepsy. Meanwhile, inhibition of neuronal firing by miR-124 was paralleled with suppression of miniature excitatory postsynaptic current (mEPSC), AMPAR-, and NMDAR-mediated currents that were associated with decreased surface expression of NMDAR.

Another recent study found that miR-219 down-regulated the expression levels of CaMKIIγ and GluN1 in hippocampal tissues of kainic acid (KA)-treated mice as compared with controls [20]. The same study showed that knockdown of miR-219 by its antagomir lead to seizure behaviors, abnormal cortical electroencephalograghy (EEG) recordings. Conversely, overexpression of miR-219 alleviated seizures and abnormal EEG recordings and suggested that miR-219 may play a potential role in ameliorating epilepsy via targeting CaMKIIγ and GluN1 [20].

We recently combined the profiling study and bioinformatics analysis to interrogate the functions of miRNAs in NMDA receptor-dependent epilepsy [10]. We observed that 18 miRNAs are differentially expressed in the rat pilocarpine model following NMDA-receptor blockade using MK-801. Of these, 16 miRNAs (miR-29c-5p, miR-376a-3p, miR-672-3p, miR-497-5p, miR-873-3p, miR-335, miR-219a-5p, miR-383-5p, miR-7a-2-3p, miR-139-3p, miR-139-5p, miR-let-7e-3p, miR-673-5p, miR-539-5p, miR-128-3p, and miR-410) were up-regulated and 2 miRNAs (miR-3473 and miR-6215) were down-regulated. We confirmed the profiling result using reverse trascription polymerase chain reaction (RT-PCR) and explored the functional significance of miRNA expression change. Interestingly, miR-139-5p, brain enriched miRNA, was statistically up-regulated and GluN2A was predicted as its potential putative target. Furthermore, miR-139-5p was statistically decreased while GluN2A and GluN2B levels were statistically up-regulated in patients with TLE. In the rat model of status epilepticus (SE), miR-139-5p expression was decreased while GluN2A was increased in the acute and chronic phases, but not in the latent phase. GluN2B expression was increased during the three phases of TLE development. Meanwhile, overexpression of miR-139-5p suppressed, while knockdown of miR-139-5p enhanced the increase in GluN2A, but not GluN2B, after pilocarpine treatment. Interestingly, MK-801 and NVP-AAM077 increased miR-139-5p levels suppressed by pilocarpine treatment, while ifenprodil was ineffective. We concluded that miR-139-5p and GluN2A subunit containing NMDA receptor are inversely correlated and miR-139-5p negatively regulates GluN2A level in pilocarpine-induced experimental model of epilepsy (Table 1). Thus, miR-139-5p is identified as a novel seizure regulator and characterized the miR-139-5p/GluN2A pathway as a potential target for preventing and treating epilepsy [10].

miRNA profiling in brain tissues of patients with mTLE revealed altered miRNA expression. miR-204 and miR-218 were found significantly down-regulated and further analysis showed that GRM1 is their target [53]. Both miR-204 and miR-218 suppressed GRM1 expression, encoding the metabotropic glutamate receptor mGluR1. Other targets related to glutamate receptors such as the neuronal GLT-1 and GNAI2 were also identified to be targets of miR-218 [53].

Overall, these findings strongly suggest that miR-124, miR-139-5p, miR-219, miR-204, and miR-218 could be new therapeutic approaches to decrease excitotoxicity associated with epilepsy.

Stroke

Stroke is the most common cause of adult disabilities among elder people and the second leading cause of death [54,55]. Cerebral ischemia involves a complex series of biological and molecular mechanisms, including excitotoxicity, which finally leads to cell death. Excitotoxicity is mainly caused by glutamate-mediated neurotoxicity that is resulted from excessive accumulation of excitatory glutamate [44]. This mechanism leads to toxic increases in intracellular calcium that mediates cell death in stroke [9,45]. Several miRNAs have been found altered in brain right after stroke as well as during reperfusion and specific targets have been identified for some of them [56,57]. Of these, miR-223 has been reported to be neuroprotective by targeting AMPA receptor subunit GluA2 and NMDA receptor subunit GluN2B, which regulates glutamate-mediated neuronal excitatory (Table 1). In the same study, overexpression of miR-223 was found to decrease neuronal loss after excitotoxic insult and its silencing was associated with up-regulation of GluA2 and GluN2B subunits that increase mEPSC amplitude and decay time and enhance NMDA-mediated Ca2+ influx and result in nitric oxide production and excitotoxicity [9].

Silva and colleagues analyzed the expression levels of miR-219 and NMDA in the blood and brain tissue of rats following cerebral ischemia associated with alcoholism [58]. They observed that miR-219 is deceased in the ischemic, alcoholic, and ischemic plus alcoholic groups in the rat brain tissues whereas NMDA receptor was increased [58]. They suggested a negative correlation between NMDA by miR-219 (Table 1). However, further studies are needed to determine whether targeting this interesting miRNA by its agomir/antagomir could affect stroke and related excitotoxicity. Therefore, it can be concluded that miR-223 and miR-219 may contribute to neuronal excitability underlying stroke. Moreover, direct delivery of these miRNAs to the neuronal cell could be a new therapeutic approach to decrease excitotoxicity and neuronal damage following stroke [59].

Notably, findings about the role of miR-132 in stroke are controversial. Recent findings have shown that miR-132 is neuroprotective from severe post-oxygen–glucose deprivation (OGD) and NMDA toxicity in which overexpression of miR-132 reduced OGD and NMDA-induced neuronal damage following of ischemic brain injury. Although cultured neurons were not protected from H2O2-mediated death but survival was significantly increased in miR-132 transduced neurons following NMDA exposure. They concluded that miR-132 may target elements of the excitotoxic pathway including NMDA [60]. In contrast, Kaur et al. [61] reported that during cerebral ischemic attacks, miR-132 is up-regulated in cultured cortical neurons, which up-regulate the expression of GluN2A, GluN2A, and GluR1 receptors [62]. This suggested that miR-132 knockdown may have a neuroprotective effect by suppressing glutamate receptor expression, thereby suppressing related excitotoxicity.

It is well documented that stroke is associated with the suppression of GLT-1 expression that regulates glutamate accumulation and neuronal cell excitotoxicity in stroke [63]. miR-107 is another well-studied miRNA in ischemic stroke. A previous study demonstrated that miR-107 is up-regulated in a focal cerebral ischemia/reperfusion injury rat model [63]. This up-regulation of miR-107 is associated with down-regulated GLT-1 expression and glutamate accumulation. Interestingly, knockdown of miR-107 blocked all of the effects, suggesting that miR-107 may inhibit GLT-1 expression which in turn enhances glutamate accumulation. In a recent study, miRNAs expression profiling demonstrated that 18 miRNAs were significantly expressed in diabetic rats following ischemic stroke [64]. Of these, miR-107, miR-145, and miR-223 were found to be biologically related to glutamate toxicity.

Other miRNAs such as, miR-181a, miR-125b, and miR-124a are up-regulated in ischemic brain (Table 1). On the other hand, these miRNAs have been reported to play potential roles in glutamate receptors and their associated proteins regulation in neurons and astrocytes [65]. Studies suggest that GluN2A is the direct target of this miR-125b in hippocampal neurons and its overexpression or inhibition results in GluN2A up- and down-regulation respectively [24,66]. For miR-181, multiple studies have shown that GluA2 and GLT-1 are regulated by miR-181a [32,36,37]. Surprisingly, although inhibition of miR-181a was found to significantly decrease the expression of levels of miR-181a and GLT-1 after forebrain ischemia, miR-181a did not directly target GLT-1 [67]. One study has shown that neuronal exosomal miR-124 can also regulate astroglial GLT-1 expression that enhances astrocytic glutamate uptake and limits excitotoxicity [35]. Evidence shows that miR-124 is significantly up-regulated in ischemic penumbra as well as in plasma. Studies also found that this miRNA is neuroprotective against the experimental stroke models [68]. Taken together, it is possible that miR-124 up-regulation in penumbra can elevate GLT1 levels to suppress excitotoxicity caused by accumulation of glutamate.

Therefore, it can be inferred from these researches that overexpression of miR-125b, miR-181, or miR-124a that occurs after stroke can modulate GluRs and transporters that promote neuronal injury and exacerbate stroke-related excitotoxicity [69]. However, further researches are required to elucidate their exact mechanisms in stroke-related excitotoxicity.

Neuroautoimmune diseases

Multiple sclerosis

MS is a chronic inflammatory autoimmune disorder that is characterized by progressive loss of structure and function of neurons [70]. Recent findings have shown that miR-142-3p leads to excitotoxic damage in both MS and experimental autoimmune encephalomyelitis (EAE), animal model of MS [71]. miR-142-3p expression was up-regulated in the EAE mice and in cerebrospinal fluid (CSF) of MS patients. More importantly, inhibition of miR-142-3p could be neuroprotective in MS by targeting glial  L-glutamate–aspartate transporter GLAST (also known as EAAT1), which causes an enhancement of the glutamatergic transmission.

Evidence shows that miR-124 targets GluA2 that plays major roles in excitatory neurotransmission in the brain [33]. In another study, miR-124 was found up-regulated in the demyelinated hippocampi of patients with MS. Furthermore, the expression of AMPA receptor, targeted by miR-124, was down-regulated dramatically in the demyelinated hippocampi [72]. These findings suggest a potential role for miR-124 in demyelination. It will therefore be of great interest to explore whether MS progression in animal models can be prevented with miR-124 activators.

Based on these findings, it is conceivable that modulation of miR-124 and miR-142-3p could be a viable strategy to decrease excitotoxicity following MS. Although evidence shows a tight link between NMDARs and multiple forms of MS [49], there are no data available that show the relationship between miRNA-related changes of NMDA receptors and excitotoxicity.

Anti-NMDA receptor encephalitis

Anti-NMDA receptor encephalitis is an autoimmune disorder in which antibodies attack NMDA-type glutamate receptors at central neuronal synapses. Among the several hundred miRNAs expressed in the human brain, the let-7 family has been discovered in the literature to be involved in anti-NMDA receptor encephalitis. The expression levels of let-7a, let-7b, let-7d, and let-7f were shown to be significantly down-regulated in anti-NMDAR encephalitis compared with the negative controls [73]. Of interest, let-7b is the unique miRNA that is significantly decreased in anti-NMDAR encephalitis but not in other neurological disease. Surprisingly, let-7b returned into normal following immunotherapy which indicates that it can be considered as a potential biomarker and an indicator that predict the treatment responses and follow-up of patients with anti-NMDAR encephalitis.

Neuropsychiatric diseases

Major depressive disorder

MDD is one of the most prevalent mood disorders. Although the principal cause of this disorder is largely unknown, many antidepressants have NMDARs channel blocking properties [7476]. Previous studies hypothesized that MDD is driven by disruptions in prominent biological pathways, particularly those contributing to the remodeling in the glutamatergic neurotransmission [77,78] and neuroplasticity mechanisms [79]. Recent evidence indicates that glutamate receptors and transporters are targeted by individual miRNAs in depression [8083]. One study indicated that miR-1202 is down-regulated in individuals with MDD compared with healthy controls while metabotropic GRM4 is up-regulated. Additionally, overexpression of miR-1202 is associated with down-regulation of GRM4. Therefore, GRM4 was identified as a target of miR-1202 in MDD [80]. Recently, another interesting study further investigated the association of rs2229901, variant located at the GRM4 3′-UTR, with MDD and identified rs2229901 as the binding site of miR-1202 in MDD patients [81]. These results suggest that the interaction between miR-1202 and GRM4 is associated with the pathophysiology of depression and is a critical approach for novel antidepressant treatments. Li et al. [82] used blood samples from MDD patients and found that miR-335 is decreased in patients with MDD compared with healthy controls. In the same study, miR-335 was reported to directly target GRM4, which can further control the expression of miR-335. Meanwhile, antidepressant drug treatment with citalopram elevated miR-335 expression and suppressed GRM4 expression. It was, therefore, concluded that miR-335 is associated with the pathophysiology of depression and may functions as a diagnostic biomarker and therapeutic agents. Wei et al. [83] used a combination of in silico and in vitro analyses and reported that miR-101b is down-regulated and targeted the up-regulated solute carrier family 1, member 1 (SLC1A1) in the flinders sensitive line (FSL) model. The FSL is a genetic model of MDD that is associated with a dysfunctional regulation of glutamate transmission and has a reduction of both neuronal and glial glutamate receptors and transporters [84,85]. SLC1A1 has also been reported to be regulated by GluN1, GluN2A, and GluN2B [86]. Of interest, GluN2A and GluN2B are down-regulated in the FSL model that may indicate a new co-regulatory mechanism [84]. Zhao et al. investigated the effect of miR-137 on the brain and peripheral blood from poststroke depression rats [87]. They found that this miRNA is down-regulated and its overexpression improved behavioral changes by targeting GluN2A (Grin2A) gene [87].

Overall, all miRNAs associated with depression are down-regulated and negatively regulated with their targets, suggesting that these miRNAs may be protective against depression.

Schizophrenia

SCZ is a chronic neuropsychiatric disorder associated with affective, cognitive, neuromorphological, and molecular abnormalities. Indeed, several studies have shown that NMDA hypofunction is tightly linked to SCZ [88,89]. Notably, NMDA receptor antagonists induce psychosis and cognitive impairment in normal human subjects [90], and produce both positive and negative SCZ-like behaviors in animal models [91]. Several miRNAs that target transcripts relevant to SCZ pathology have been explored. Recent studies have found several miRNA species associated with NMDA receptor-dependent SCZ. Miller et al. [92] reported that administration of an NMDA antagonist resulted in down-regulation of miR-132 and up-regulation of multiple miR-132 targets in the PFC. Moreover, the predicted miR-132 gene targets may interact with SCZ candidate genes such as GRIN1, GRIN2A, and GRIN2B [93]. Zhang et al. [94] conducted a study on Chinese Han population and reported that GRIN2B is involved in SCZ. This study also suggested that interaction effects of the polymorphisms in hsa-miR-219, CAMK2G, GRIN2B, and GRIN3A may indicate susceptibility to SCZ. miR-219 was also identified as a regulator of CaMKIIγ following dizocilpine-mediated NMDA receptor hypofunction [19]. Dizocilpine is the most common NMDAR antagonist used in laboratories that may rapidly cause SCZ-like behavioral deficits [95], which supports the possible role of miR-219 in SCZ. In another study, Beveridge et al. observed that miR-107 is up-regulated in dorsolateral prefrontal cortex (DLFC) from patients with SCZ and is identified to have a strong regulation effect on 3′-UTR elements from GluN3A (GRIN3A) [96]. In addition, miR-107 is highly enriched in pathways associated with synaptic plasticity and neural connectivity [96].

Therefore, it appears that miR-132, miR-219, and miR-107 may be important mediators in the NMDA receptor-dependent SCZ. Although previous studies found a link between SCZ and other glutamate receptors such as AMPA and mGluRs [97], there is no prior report on the role of miRNAs in this process.

Alzheimer’s disease

AD is the most common cause of dementia that is characterized by progressive deterioration of cognition function, profound memory impairment and changes in personality and behavior. Both iGluRs and mGluRs have been associated with AD [4648]. Recently, up-regulation of miRNA 34a in the hippocampus has been proved to be involved in anxiety-like behavior in a triple transgenic mouse model of AD. This up-regulation is associated with down-regulation of mGluR7 (GRM7) gene but not fibroblast growth factor-2 (FGF2). This indicates that anxiety-like behavior occurred in AD with an involvement of miR-34a and GRM7 [98]. Accumulating evidence has suggested that mGluR7 is neuroprotective against AD-associated excitotoxicity and loss of basal forebrain (BF) cholinergic neurons by suppression of NMDA currents [47]. Moreover, evidence showed that amyloid-β (Aβ) oligomers lead to synaptotoxic effects by NMDA receptors [48]. Taking together, knockdown of miR-34a may activate the GRM7 in AD that leads to suppress the increase in NMDA receptor after Aβ toxicity. In another study, miR-34a was also found to play a critical role in cell proliferation, morphology, and function of developing neurons, and ultimately enhances behavioral functions by inhibiting the density of NMDA-evoked currents [22]. These results support the neuroprotective role of miR-34a in AD through modulating excitotoxicity. Brain-enriched miR-153 was found down-regulated in a subset of AD patients, and its specific target was identified as amyloid precursor protein (APP) expression [99]. Of interest, miR-153 was also found to regulate GluA1 expression and its knockdown enhanced memory in mice [30]. This suggests that this miRNA may play a role in memory deficits associated with AD and more studies, however, are required to investigate its role in AD in relation to exitotoxicity. It was found that miR-137 is associated with intellectual disability [100]. Another study showed that miR-137 can regulate AMPA receptor (GluA1) and mGluR5 suggesting that glutamatergic dysfunction may play a role in the pathogenesis of miR-137-linked cognitive impairments [31]. On the other hand, a considerable amount of research has been devoted to miR-137 dysregulation in AD. Geekiyanage et al. [101] found that miR-137 expression is down-regulated in the brain and serum of patients with AD. Taken together, it is highly plausible that miR-137 has anti-AD effects by regulation of AMPA receptor and/or mGluR5. It will, therefore, be of great interest to evaluate whether miR-137 inhibitors can be neuroprotective against AD-associated excitotoxicity in animal models.

Fragile X syndrome

FXS is an inherited form of mental retardation caused by transcriptional inactivation of fragile X mental retardation 1 (FMR1) gene. This results in a loss of FMRP expression that is required for regulating normal neuronal connectivity and plasticity. FMRP was recently reported to affect NMDAR signaling via a negatively regulatory mechanism involving miR-125b and miR-132 [24]. Specifically, overexpression of miR-125b was found to down-regulate GluN2A expression, but no effect was observed on the levels of GluN2B or GluN1. FMRP interacts with miRNAs like miR-125 and miR-132 during neuronal development to modulate the signaling of mGluR1 and NMDAR respectively [102].

Neuropathic pain

Neuropathic pain is a chronic pain that develops as a result of lesions or disease affecting the somatosensory nerve system. Previous researches have indicated that miRNAs such as miR-96 and miR-182 may contribute to neuropathic pain [103,104]. On the other hand, GluA2 trafficking in the periaqueductal gray could modulate pain, and potent analgesic effects were observed in rat model by inhibiting GluA2 endocytosis [50]. Additionally, AMPA receptor subunits were found to be up-regulated in dorsal root ganglion following nerve injury [105]. In a recent study by Xie et al. [34], overexpression of miR-183 was found to inhibit AMPA receptors GluA1 and GluA2 by suppression mTOR/VEGF pathway which in turn can significantly relieve neuropathic pain in chronic compress injury model. Surprisingly, despite many studies have reported the role of NMDAR in neuropathic pain [106], there is no prior report on the role of NMDAR-dependent regulation of miRNAs in this disease.

Therapeutic applications and challenges

To date, two direct strategies to develop miRNA-based therapeutics were identified: (i) mimics or agomirs that intended to enhance miRNA function and increase its effective level and (ii) inhibitors or antagomirs to block endogenous levels of miRNAs to enhance its targets. Several functional studies using agomirs/antagomirs reported miRNAs as novel potential approaches to treat a plenty of neurological diseases by modulating excitotoxicity.

The majority of miRNAs that have been reported involved in glutamate receptor-dependent neurological diseases are mostly down-regulated and their targets are up-regulated (Table 2). miR-9, miR-124a/b, miR-134, miR-135a/b, miR-153, miR-183, and miR-219 were observed to be expressed exclusively in differentiating neurons such as [107]. This suggests that these miRNAs may play a conserved role in neuronal processes. Furthermore, some miRNAs including miR-9, miR-125a/b, miR-128, miR-132, miR-137, and miR-139 were observed to be highly enriched in brain with some scattered expression in other organs, which suggests their participation in developmental and physiological pathways within the brain [107]. It is important to note that several microRNAs are involved in more than one disease discussed in this review such as brain-specific miR-219 and miR-124, and brain-enriched miR-137 and miR-132. Brain-specific miR-219, for example, is associated with epilepsy [20], cerebral ischemia [58], SCZ [94], and neurobehavioral dysfunction [19]. Similarly, brain-specific miR-124 is implicated in epilepsy [52] and MS [72], while brain-enriched miR-132, miR-219, and miR-107 are implicated in cerebral ischemia [58,60,63] and SCZ [92,94,96]. In addition, brain-enriched miR-137 has been identified in MDD and cognitive impairments [31,87]. Therefore, researchers should focus on these brain-specific and enriched miRNAs due to their ability to regulate several different pathways. On the other hand, a number of miRNAs target more than one gene of the glutamate receptors. For example, miR-124 targets both NMDA and AMPA receptors while miR-219 targets NMDA receptor, GluN1, GluN2B, and CaMKIIγ. Interestingly, miR-132 is involved in several diseases by targeting a specific receptor, NMDAR.

Several studies have recently shown the correlation between iGluRs and miRNAs in neurological diseases. NMDAR was found to be targeted by miR-124, miR-132, let-7, and miR-219 [52,60,73,19], while AMPAR was reregulated by miR-124 and miR-183 [34,72]. GluN2A subunit is the most iGluRs subunit targeted by miRNAs in neurological disorders. It was targeted by three brain-enriched miRNAs (miR-139-5p, miR-125b, and miR-137) in three different neurological diseases including TLE, FXS, and poststroke depression respectively [10,24,87]. GluN2B subunit was targeted by miR-223 and miR-219 in two different neurological diseases including cerebral ischemia and SCZ respectively [9,94], while GluN3A was only regulated by miR-107 in SCZ [96]. Notably, miR-219 is the only miRNA that was found targeting GluN1 subunit in two different neurological diseases including epilepsy and cerebral ischemia [20,58]. miR-223 and miR-183 have a protective effect against cerebral ischemia and neuropathic pain respectively, by targeting GluA2 as well as other glutamate receptors [9,34]. For GluA2 subunit, it can be targeted by miR-183 to play a protective role in neuropathic pain [34], and regulated by miR-137 to contribute to the pathogenesis of cognitive impairments [31]. mGluRs subunits were also found to be regulated by miRNAs in neurological disorders. GRM1 was found to be targeted by miR-204 and miR-218 during mTLE, and GRM4 was regulated by miR-335 and miR-1202 in MDD, while GRM7 was targeted by miR-34a in AD. These findings indicate that modulation of above-mentioned miRNAs, individually or in combination, and related genes may exert neuroprotective and/or disease-modifying effects.

Despite the positive findings noted above, the fact remains that several obstacles are associated with the therapeutic use of miRNA such as blood–brain barrier (BBB), glomerular filtration, and hepatic metabolism. There is growing evidence that endogenous miRNAs can modulate the function of BBB. Recent studies have shown that minoxidil sulfates, exosomes, APP, or low-density lipoprotein receptor-related protein 1 (LRP-1) can serve as good delivery agents for miRNAs across the BBB by various mechanisms.

Conclusions and outlook

Current available data indicate significant regulatory roles of miRNAs in the pathogenesis of glutamate receptor-dependent neurological disorders. Such data promise to achieve a new level of understanding on how glutamate receptors is involved in neurological diseases and will aid in defining how miRNAs mediate these diseases. miRNAs contribute to neuroprotection, synaptic transmission and plasticity, neuronal development, and dendritic spines. Thus, modulation of miRNAs discussed in this review may be applied to positively affect the complex neurological diseases outcomes by controlling excitotoxicity. However, more researches should be performed on the pharmacokinetics of miRNA in the body to understand the threshold copies of miRNA that should be replaced or repressed in each disease state.

Acknowledgments

We gratefully acknowledge the excellent assistance of Ezzadeen F. and Alsharafi A. We also thank Al-garadi for critical reading of the manuscript.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Abbreviations

     
  • amyloid-β

  •  
  • AD

    Alzheimer’s disease

  •  
  • AGO

    argonaute

  •  
  • AIDA

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

  •  
  • AMPAR

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

  •  
  • AP5

    2R-amino-5-phosphonovaleric acid

  •  
  • APP

    amyloid precursor protein

  •  
  • BBB

    blood–brain barrier

  •  
  • BDNF

    brain-derived neurotrophic factor

  •  
  • CaMKIIγ

    Ca2+/calmodulin-dependent protein kinase IIγ

  •  
  • CNS

    central nervous system

  •  
  • CSF

    cerebrospinal fluid

  •  
  • DGCR8

    DiGeorge syndrome critical region 8

  •  
  • EAAT2

    excitatory amino acid transporter

  •  
  • EAE

    experimental autoimmune encephalomyelitis

  •  
  • EEG

    electroencephalography

  •  
  • FGF2

    fibroblast growth factor-2

  •  
  • FMRP

    fragile X mental retardation protein

  •  
  • FSL

    Flinders sensitive line

  •  
  • FXS

    fragile X syndrome

  •  
  • GluR

    glutamate receptor

  •  
  • GLAST

    L-glutamate/L-aspartate transporter

  •  
  • GLT-1

    glutamate transporter-1

  •  
  • GRM4

    glutamate receptor 4

  •  
  • iGluR

    ionotropic glutamate receptor

  •  
  • KA

    kainic acide

  •  
  • LRP-1

    low-density lipoprotein receptor-related protein 1

  •  
  • LTD

    long-term depression

  •  
  • LTP

    long-term potentiation

  •  
  • MDD

    major depressive disorder

  •  
  • mEPSC

    miniature excitatory postsynaptic current

  •  
  • mGluR

    metabotropic glutamate receptor

  •  
  • mRNA

    messenger RNA

  •  
  • MS

    multiple sclerosis

  •  
  • mTLE

    mesial temporal lobe epilepsy

  •  
  • mTOR

    mammalian target of rapamycin

  •  
  • NMDA

    N-methyl-D-aspartate

  •  
  • OGD

    post-oxygen–glucose deprivation

  •  
  • Pre-miRNA

    precursor miRNA

  •  
  • Pri-miRNA

    primary miRNA

  •  
  • REST

    repressor element 1 silencing transcription factor

  •  
  • RISC

    RNA-induced silencing complex

  •  
  • RT-PCR

    reverse trascription polymerase chain reaction

  •  
  • SCZ

    schizophrenia

  •  
  • SE

    staus epilepticus

  •  
  • SLC1A1

    solute carrier family 1, member 1

  •  
  • VEGF

    vascular endothelial growth factor

  •  
  • VGlut

    vesicular glutamate transporter

References

References
1
Hamilton
A.
,
Zamponi
G.W.
and
Ferguson
S.S.
(
2015
)
Glutamate receptors function as scaffolds for the regulation of β-amyloid and cellular prion protein signaling complexes
.
Molecular Brain
8
,
18
2
Levite
M.
(
2014
)
Glutamate receptor antibodies in neurological diseases: anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies, anti-NMDA-NR2A/B antibodies, anti-mGluR1 antibodies or anti-mGluR5 antibodies are present in subpopulations of patients with either: epilepsy, encephalitis, cerebellar ataxia, systemic lupus erythematosus (SLE) and neuropsychiatric SLE, Sjogren’s syndrome, schizophrenia, mania or stroke. These autoimmune anti-glutamate receptor antibodies can bind neurons in few brain regions, activate glutamate
.
J. Neural Transm.
121
,
1029
1075
3
Ribeiro
F.M.
,
Paquet
M.
,
Cregan
S.P.
and
Ferguson
S.S.
(
2010
)
Group I metabotropic glutamate receptor signalling and its implication in neurological disease
.
CNS Neurol. Disord. Drug Targets
9
,
574
595
4
Bittigau
P.
and
Ikonomidou
C.
(
1997
)
Topical review: glutamate in neurologic diseases
.
J. Child. Neurol.
12
,
471
485
5
Alsharafi
W.A.
,
Xiao
B.
,
Abuhamed
M.M.
and
Luo
Z.
(
2015
)
miRNAs: biological and clinical determinants in epilepsy
.
Front. Mol. Neurosci.
8
,
59
6
Mirzaei
H.
,
Momeni
F.
,
Saadatpour
L.
,
Sahebkar
A.
,
Goodarzi
M.
,
Masoudifar
A.
et al
(
2017
)
MicroRNA: relevance to stroke diagnosis, prognosis and therapy
.
J. Cell. Physiol.
7
Chaudhuri
A.D.
and
Yelamanchili
S.V.
(
2017
)
MicroRNA implications in neurodegenerative disorders
. In
Neuroimmune Pharmacology
, pp.
329
341
,
Springer International Publishing
8
Junker
A.
,
Hohlfeld
R.
and
Meinl
E.
(
2011
)
The emerging role of microRNAs in multiple sclerosis
.
Nat. Rev. Neurol.
7
,
56
59
9
Harraz
M.M.
,
Eacker
S.M.
,
Wang
X.
,
Dawson
T.M.
and
Dawson
V.L.
(
2012
)
MicroRNA-223 is neuroprotective by targeting glutamate receptors
.
Proc. Natl. Acad. Sci. U.S.A.
109
,
18962
18967
10
Alsharafi
W.A.
,
Xiao
B.
and
Li
J.
(
2016
)
MicroRNA-139-5p negatively regulates NR2A-containing NMDA receptor in the rat pilocarpine model and patients with temporal lobe epilepsy
.
Epilepsia
57
,
1931
1940
11
Lee
Y.
,
Kim
M.
,
Han
J.
,
Yeom
K.H.
,
Lee
S.
,
Baek
S.H.
et al
(
2004
)
MicroRNA genes are transcribed by RNA polymerase II
.
EMBO J.
23
,
4051
4060
12
Lee
Y.
,
Ahn
C.
,
Han
J.
,
Choi
H.
,
Kim
J.
,
Yim
J.
et al
(
2003
)
The nuclear RNase III Drosha initiates microRNA processing
.
Nature
425
,
415
419
13
Hutvágner
G.
,
McLachlan
J.
,
Pasquinelli
A.E.
,
Bálint
É.
,
Tuschl
T.
and
Zamore
P.D.
(
2001
)
A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA
.
Science
293
,
834
838
14
Grishok
A.
,
Pasquinelli
A.E.
,
Conte
D.
,
Li
N.
,
Parrish
S.
,
Ha
I.
et al
(
2001
)
Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans developmental timing
.
Cell
106
,
23
34
15
Vasudevan
S.
,
Tong
Y.
and
Steitz
J.A.
(
2007
)
Switching from repression to activation: microRNAs can up-regulate translation
.
Science
318
,
1931
1934
16
Julio-Pieper
M.
,
Flor
P.J.
,
Dinan
T.G.
and
Cryan
J.F.
(
2011
)
Exciting times beyond the brain: metabotropic glutamate receptors in peripheral and non-neural tissues
.
Pharmacol. Rev.
63
,
35
58
17
Traynelis
S.F.
,
Wollmuth
L.P.
,
McBain
C.J.
,
Menniti
F.S.
,
Vance
K.M.
,
Ogden
K.K.
et al
(
2010
)
Glutamate receptor ion channels: structure, regulation, and function
.
Pharmacol. Rev.
62
,
405
496
18
Conn
P.J.
and
Pin
J.P.
(
1997
)
Pharmacology and functions of metabotropic glutamate receptors
.
Annu. Rev. Pharmacol. Toxicol.
37
,
205
237
19
Kocerha
J.
,
Faghihi
M.A.
,
Lopez-Toledano
M.A.
,
Huang
J.
,
Ramsey
A.J.
,
Caron
M.G.
et al
(
2009
)
MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction
.
Proc. Natl. Acad. Sci. U.S.A.
106
,
3507
3512
20
Zheng
H.
,
Tang
R.
,
Yao
Y.
,
Ji
Z.
,
Cao
Y.
,
Liu
Z.
et al
(
2016
)
MiR-219 protects against seizure in the kainic acid model of epilepsy
.
Mol. Neurobiol.
53
,
1
7
21
Wibrand
K.
,
Panja
D.
,
Tiron
A.
,
Ofte
M.L.
,
Skaftnesmo
K.O.
,
Lee
C.S.
et al
(
2010
)
Differential regulation of mature and precursor microRNA expression by NMDA and metabotropic glutamate receptor activation during LTP in the adult dentate gyrus in vivo
.
Eur. J. Neurosci.
31
,
636
645
22
Mollinari
C.
,
Racaniello
M.
,
Berry
A.
,
Pieri
M.
,
De Stefano
M.C.
,
Cardinale
A.
et al
(
2015
)
miR-34a regulates cell proliferation, morphology and function of newborn neurons resulting in improved behavioural outcomes
.
Cell Death Dis.
6
,
e1622
23
Corbel
C.
,
Hernandez
I.
,
Wu
B.
and
Kosik
K.S.
(
2015
)
Developmental attenuation of N-methyl-D-aspartate receptor subunit expression by microRNAs
.
Neural Dev.
10
,
20
24
Edbauer
D.
,
Neilson
J.R.
,
Foster
K.A.
,
Wang
C.F.
,
Seeburg
D.P.
,
Batterton
M.N.
et al
(
2010
)
Regulation of synaptic structure and function by FMRP-associated microRNAs miR-125b and miR-132
.
Neuron
65
,
373
384
25
Hu
Z.
,
Yu
D.
,
Gu
Q.H.
,
Yang
Y.
,
Tu
K.
,
Zhu
J.
et al
(
2014
)
miR-191 and miR-135 are required for long-lasting spine remodelling associated with synaptic long-term depression
.
Nat. Commun.
5
,
3263
26
Hu
Z.
,
Zhao
J.
,
Hu
T.
,
Luo
Y.
,
Zhu
J.
and
Li
Z.
(
2015
)
miR-501-3p mediates the activity-dependent regulation of the expression of AMPA receptor subunit GluA1
.
J. Cell Biol.
208
,
949
959
27
Gu
Q.H.
,
Yu
D.
,
Hu
Z.
,
Liu
X.
,
Yang
Y.
,
Luo
Y.
et al
(
2015
)
miR-26a and miR-384-5p are required for LTP maintenance and spine enlargement
.
Nat. Comm.
6
,
6789
28
Yelamanchili
S.V.
,
Chaudhuri
A.D.
,
Chen
L.N.
,
Xiong
H.
and
Fox
H.S.
(
2010
)
MicroRNA-21 dysregulates the expression of MEF2C in neurons in monkey and human SIV/HIV neurological disease
.
Cell Death Dis.
1
,
e77
29
Letellier
M.
,
Elramah
S.
,
Mondin
M.
,
Soula
A.
,
Penn
A.
,
Choquet
D.
et al
(
2014
)
miR-92a regulates expression of synaptic GluA1-containing AMPA receptors during homeostatic scaling
.
Nat. Neurosci.
17
,
1040
1042
30
Mathew
R.S.
,
Tatarakis
A.
,
Rudenko
A.
,
Johnson-Venkatesh
E.M.
,
Yang
Y.J.
,
Murphy
E.A.
et al
(
2016
)
A microRNA negative feedback loop downregulates vesicle transport and inhibits fear memory
.
eLife
5
,
e22467
31
Loohuis
N.F.
,
Ba
W.
,
Stoerchel
P.H.
,
Kos
A.
,
Jager
A.
,
Schratt
G.
et al
(
2015
)
MicroRNA-137 controls AMPA-receptor-mediated transmission and mGluR-dependent LTD
.
Cell Rep.
11
,
1876
84
32
Saba
R.
,
Störchel
P.H.
,
Aksoy-Aksel
A.
,
Kepura
F.
,
Lippi
G.
,
Plant
T.D.
et al
(
2012
)
Dopamine-regulated microRNA MiR-181a controls GluA2 surface expression in hippocampal neurons
.
Mol. Cell Biol.
32
,
619
632
33
Ho
V.M.
,
Dallalzadeh
L.O.
,
Karathanasis
N.
,
Keles
M.F.
,
Vangala
S.
,
Grogan
T.
et al
(
2014
)
GluA2 mRNA distribution and regulation by miR-124 in hippocampal neurons
.
Mol. Cell. Neurosci.
61
,
1
12
34
Xie
X.
,
Ma
L.
,
Xi
K.
,
Fan
D.
and
Zhang
W.
(
2017
)
MicroRNA-183 suppresses neuropathic pain and expression of AMPA receptors by targeting mTOR/VEGF signaling pathway
.
Cell. Physiol. Biochem.
41
,
181
192
35
Morel
L.
,
Regan
M.
,
Higashimori
H.
,
Ng
S.K.
,
Esau
C.
,
Vidensky
S.
et al
(
2013
)
Neuronal exosomal miRNA-dependent translational regulation of astroglial glutamate transporter GLT1
.
J. Biol. Chem.
288
,
7105
7116
36
Follert
P.
,
Cremer
H.
and
Béclin
C.
(
2014
)
MicroRNAs in brain development and function: a matter of flexibility and stability
.
Front. Mol. Neurosci.
7
,
5
37
Ouyang
Y.B.
,
Xu
L.
,
Liu
S.
and
Giffard
R.G.
(
2014
)
Role of astrocytes in delayed neuronal death: GLT-1 and its novel regulation by microRNAs
. In
Glutamate and ATP at the Interface of Metabolism and Signaling in the Brain
, pp.
171
188
,
Springer International Publishing
38
Karr
J.
,
Vagin
V.
,
Chen
K.
,
Ganesan
S.
,
Olenkina
O.
,
Gvozdev
V.
et al
(
2009
)
Regulation of glutamate receptor subunit availability by microRNAs
.
J. Cell Biol.
185
,
685
697
39
Ryan
B.
,
Logan
B.J.
,
Abraham
W.C.
and
Williams
J.M.
(
2017
)
MicroRNAs, miR-23a-3p and miR-151-3p, are regulated in Dentate Gyrus Neuropil following induction of long-term potentiation in vivo
.
PLoS ONE
12
,
e0170407
40
Pichardo-Casas
I.
,
Goff
L.A.
,
Swerdel
M.R.
,
Athie
A.
,
Davila
J.
,
Ramos-Brossier
M.
et al
(
2012
)
Expression profiling of synaptic microRNAs from the adult rat brain identifies regional differences and seizure-induced dynamic modulation
.
Brain Res.
1436
,
20
33
41
Ryan
M.M.
,
Ryan
B.
,
Kyrke-Smith
M.
,
Logan
B.
,
Tate
W.P.
,
Abraham
W.C.
et al
(
2012
)
Temporal profiling of gene networks associated with the late phase of long-term potentiation in vivo
.
PLoS ONE
7
,
e40538
42
Verma
P.
,
Augustine
G.J.
,
Ammar
M-R.
,
Tashiro
A.
and
Cohen
S.M.
(
2015
)
A neuroprotective role for microRNA miR-1000 mediated by limiting glutamate excitotoxicity
.
Nat. Neurosci.
18
,
379
385
43
Mathern
G.W.
,
Pretorius
J.K.
,
Kornblum
H.I.
,
Mendoza
D.
,
Lozada
A.
,
Leite
J.P.
et al
(
1997
)
Human hippocampal AMPA and NMDA mRNA levels in temporal lobe epilepsy patients
.
Brain
120
,
1937
1959
44
Lai
T.W.
,
Zhang
S.
and
Wang
Y.T.
(
2014
)
Excitotoxicity and stroke: identifying novel targets for neuroprotection
.
Prog. Neurobiol.
115
,
157
188
45
Mehta
S.L.
,
Manhas
N.
and
Raghubir
R.
(
2007
)
Molecular targets in cerebral ischemia for developing novel therapeutics
.
Brain Res. Rev.
54
,
34
66
46
Ribeiro
F.M.
,
Vieira
L.B.
,
Pires
R.G.
,
Olmo
R.P.
and
Ferguson
S.S.
(
2017
)
Metabotropic glutamate receptors and neurodegenerative diseases
.
Pharmacol. Res.
115
,
179
191
47
Gu
Z.
,
Cheng
J.
,
Zhong
P.
,
Qin
L.
,
Liu
W.
and
Yan
Z.
(
2014
)
Aβ selectively impairs mGluR7 modulation of NMDA signaling in basal forebrain cholinergic neurons: implication in Alzheimer’s disease
.
J. Neurosci.
34
,
13614
13628
48
Shankar
G.M.
,
Bloodgood
B.L.
,
Townsend
M.
,
Walsh
D.M.
,
Selkoe
D.J.
and
Sabatini
B.L.
(
2007
)
Natural oligomers of the Alzheimer amyloid-β protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway
.
J. Neurosci.
27
,
2866
2875
49
Rossi
S.
,
Studer
V.
,
Moscatelli
A.
,
Motta
C.
,
Coghe
G.
,
Fenu
G.
et al
(
2013
)
Opposite roles of NMDA receptors in relapsing and primary progressive multiple sclerosis
.
PLoS ONE
8
,
e67357
50
Liu
T.Y.
,
Cheng
Y.
,
Qin
X.Y.
and
Yu
L.C.
(
2015
)
Pharmacologically inhibiting GluR2 internalization alleviates neuropathic pain
.
Neurosci. Bull.
31
,
611
616
51
McCormick
D.A.
and
Contreras
D.
(
2001
)
On the cellular and network bases of epileptic seizures
.
Annu. Rev. Physiol.
63
,
815
846
52
Wang
W.
,
Wang
X.
,
Zhang
Y.
,
Xu
Z.
,
Liu
J.
,
Jiang
G.
et al
(
2016
)
The microRNA miR-124 suppresses seizure activity and regulates CREB1 activity
.
Exp. Rev. Mol. Med.
18
,
e4
53
Kaalund
S.S.
,
Venø
M.T.
,
Bak
M.
,
Møller
R.S.
,
Laursen
H.
,
Madsen
F.
et al
(
2014
)
Aberrant expression of miR‐218 and miR‐204 in human mesial temporal lobe epilepsy and hippocampal sclerosis—Convergence on axonal guidance
.
Epilepsia
55
,
2017
2027
54
Ovbiagele
B.
and
Nguyen-Huynh
M.N.
(
2011
)
Stroke epidemiology: advancing our understanding of disease mechanism and therapy
.
Neurotherapeutics
8
,
319
55
Farhoudi
M.
,
Mehrvar
K.
,
Sadigh-Eteghad
S.
,
Majdi
A.
and
Mahmoudi
J.
(
2014
)
A review on molecular mechanisms of reocclusion following thrombolytic therapy in ischemic stroke patients
.
J. Exp. Clin. Neurosci. (JECNS)
1
,
1
56
Liu
D.Z.
,
Tian
Y.
,
Ander
B.P.
,
Xu
H.
,
Stamova
B.S.
,
Zhan
X.
et al
(
2010
)
Brain and blood microRNA expression profiling of ischemic stroke, intracerebral hemorrhage, and kainate seizures
.
J. Cerebral Blood Flow Metab.
30
,
92
101
57
Lim
K.Y.
,
Chua
J.H.
,
Tan
J.R.
,
Swaminathan
P.
,
Sepramaniam
S.
,
Armugam
A.
et al
(
2010
)
MicroRNAs in cerebral ischemia
.
Transl. Stroke Res.
1
,
287
303
58
Silva
C.I.
,
Novais
P.C.
,
Rodrigues
A.R.
,
Carvalho
C.A.
,
Colli
B.O.
,
Carlotti
C.G.
Jr
et al
(
2017
)
Expression of NMDA receptor and microRNA-219 in rats submitted to cerebral ischemia associated with alcoholism
.
Arq. Neuropsiquiatr.
75
,
30
35
59
Majid
A.
(
2014
)
Neuroprotection in stroke: past, present, and future
.
ISRN Neurol.
2014
,
515716
60
Keasey
M.P.
,
Scott
H.L.
,
Bantounas
I.
,
Uney
J.B.
and
Kelly
S.
(
2016
)
MiR-132 is upregulated by ischemic preconditioning of cultured hippocampal neurons and protects them from subsequent OGD toxicity
.
J. Mol. Neurosci.
59
,
404
410
61
Kaur
P.
,
Liu
F.
,
Tan
J.R.
,
Lim
K.Y.
,
Sepramaniam
S.
,
Karolina
D.S.
et al
(
2013
)
Non-coding RNAs as potential neuroprotectants against ischemic brain injury
.
Brain Sci.
3
,
360
395
62
Kawashima
H.
,
Numakawa
T.
,
Kumamaru
E.
,
Adachi
N.
,
Mizuno
H.
,
Ninomiya
M.
et al
(
2010
)
Glucocorticoid attenuates brain-derived neurotrophic factor-dependent upregulation of glutamate receptors via the suppression of microRNA-132 expression
.
Neuroscience
165
,
1301
1311
63
Yang
Z.B.
,
Zhang
Z.
,
Li
T.B.
,
Lou
Z.
,
Li
S.Y.
,
Yang
H.
et al
(
2014
)
Up-regulation of brain-enriched miR-107 promotes excitatory neurotoxicity through down-regulation of glutamate transporter-1 expression following ischaemic stroke
.
Clin. Sci.
127
,
679
689
64
Altintas
O.
,
Ozgen Altintas
M.
,
Kumas
M.
and
Asil
T.
(
2016
)
Neuroprotective effect of ischemic preconditioning via modulating the expression of cerebral miRNAs against transient cerebral ischemia in diabetic rats
.
Neurol. Res.
38
,
1003
1011
65
Majdi
A.
,
Mahmoudi
J.
,
Sadigh-Eteghad
S.
,
Farhoudi
M.
and
Shotorbani
S.S.
(
2016
)
The interplay of microRNAs and post-ischemic glutamate excitotoxicity: an emergent research field in stroke medicine
.
Neurol. Sci.
37
,
1765
1771
66
Eacker
S.M.
,
Dawson
T.M.
and
Dawson
V.L.
(
2013
)
The interplay of microRNA and neuronal activity in health and disease
.
Front. Cell. Neurosci.
7
,
1
9
67
Moon
J.M.
,
Xu
L.
and
Giffard
R.G.
(
2013
)
Inhibition of microRNA-181 reduces forebrain ischemia-induced neuronal loss
.
J. Cerebral Blood Flow Metab.
33
,
1976
1982
68
Sun
Y.
,
Gui
H.
,
Li
Q.
,
Luo
Z.M.
,
Zheng
M.J.
,
Duan
J.L.
et al
(
2013
)
MicroRNA‐124 Protects Neurons Against Apoptosis in Cerebral Ischemic Stroke
.
CNS Neurosci. Therap.
19
,
813
819
69
Wang
Y.
,
Zhang
Y.
,
Huang
J.
,
Chen
X.
,
Gu
X.
,
Wang
Y.
et al
(
2014
)
Increase of circulating miR-223 and insulin-like growth factor-1 is associated with the pathogenesis of acute ischemic stroke in patients
.
BMC Neurol.
14
,
77
70
Huang
Q.
,
Xiao
B.
,
Ma
X.
,
Qu
M.
,
Li
Y.
,
Nagarkatti
P.
et al
(
2016
)
MicroRNAs associated with the pathogenesis of multiple sclerosis
.
J. Neuroimmunol.
295
,
148
161
71
Mandolesi
G.
,
De Vito
F.
,
Musella
A.
,
Gentile
A.
,
Bullitta
S.
,
Fresegna
D.
et al
(
2017
)
miR-142-3p is a key regulator of IL-1β-dependent synaptopathy in neuroinflammation
.
J. Neurosci.
37
,
546
561
72
Dutta
R.
,
Chomyk
A.M.
,
Chang
A.
,
Ribaudo
M.V.
,
Deckard
S.A.
,
Doud
M.K.
et al
(
2013
)
Hippocampal demyelination and memory dysfunction are associated with increased levels of the neuronal microRNA miR‐124 and reduced AMPA receptors
.
Ann. Neurol.
73
,
637
645
73
Zhang
J.
,
Xu
X.
,
Zhao
S.
,
Gong
Z.
,
Liu
P.
,
Guan
W.
et al
(
2015
)
The expression and significance of the plasma Let-7 Family in Anti-N-methyl-d-aspartate Receptor Encephalitis
.
J. Mol. Neurosci.
56
,
531
539
74
Barygin
O.I.
,
Nagaeva
E.I.
,
Tikhonov
D.B.
,
Belinskaya
D.A.
,
Vanchakova
N.P.
and
Shestakova
N.N.
(
2017
)
Inhibition of the NMDA and AMPA receptor channels by antidepressants and antipsychotics
.
Brain Res.
1660
,
58
66
75
Nowak
G.
,
Trullas
R.
,
Layer
R.T.
,
Skolnick
P.H.I.L.
and
Paul
I.A.
(
1993
)
Adaptive changes in the N-methyl-D-aspartate receptor complex after chronic treatment with imipramine and 1-aminocyclopropanecarboxylic acid
.
J. Pharmacol. Exp. Ther.
265
,
1380
1386
76
Skolnick
P.
(
1999
)
Antidepressants for the new millennium
.
Eur. J. Pharmacol.
375
,
31
40
77
Popoli
M.
,
Yan
Z.
,
McEwen
B.S.
and
Sanacora
G.
(
2012
)
The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission
.
Nat. Rev. Neurosci.
13
,
22
37
78
Sanacora
G.
,
Treccani
G.
and
Popoli
M.
(
2012
)
Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders
.
Neuropharmacology
62
,
63
77
79
Tardito
D.
,
Perez
J.
,
Tiraboschi
E.
,
Musazzi
L.
,
Racagni
G.
and
Popoli
M.
(
2006
)
Signaling pathways regulating gene expression, neuroplasticity, and neurotrophic mechanisms in the action of antidepressants: a critical overview
.
Pharmacol. Rev.
58
,
115
134
80
Lopez
J.P.
,
Lim
R.
,
Cruceanu
C.
,
Crapper
L.
,
Fasano
C.
,
Labonte
B.
et al
(
2014
)
miR-1202 is a primate-specific and brain-enriched microRNA involved in major depression and antidepressant treatment
.
Nat. Med.
20
,
764
768
81
Dadkhah
T.
,
Rahimi-Aliabadi
S.
,
Jamshidi
J.
,
Ghaedi
H.
,
Taghavi
S.
,
Shokraeian
P.
et al
(
2017
)
A genetic variant in miRNA binding site of glutamate receptor 4, metabotropic (GRM4) is associated with increased risk of major depressive disorder
.
J. Affect Disord.
208
,
218
222
82
Li
J.
,
Meng
H.
,
Cao
W.
and
Qiu
T.
(
2015
)
MiR-335 is involved in major depression disorder and antidepressant treatment through targeting GRM4
.
Neurosci. Lett.
606
,
167
172
83
Wei
Y.B.
,
Melas
P.A.
,
Villaescusa
J.C.
,
Liu
J.J.
,
Xu
N.
,
Christiansen
S.H.
et al
(
2016
)
MicroRNA 101b is downregulated in the prefrontal cortex of a genetic model of depression and targets the glutamate transporter SLC1A1 (EAAT3) in vitro
.
Int. J. Neuropsychopharmacolog.
19
,
pyw069
84
Eriksson
T.M.
,
Delagrange
P.
,
Spedding
M.
,
Popoli
M.
,
Mathé
A.A.
,
Ögren
S.O.
et al
(
2012
)
Emotional memory impairments in a genetic rat model of depression: involvement of 5-HT/MEK/Arc signaling in restoration
.
Mol. Psychiatry
17
,
173
184
85
Gómez-Galán
M.
,
De Bundel
D.
,
Van Eeckhaut
A.
,
Smolders
I.
and
Lindskog
M.
(
2013
)
Dysfunctional astrocytic regulation of glutamate transmission in a rat model of depression
.
Mol. Psychiatry
18
,
582
594
86
Waxman
E.A.
,
Baconguis
I.
,
Lynch
D.R.
and
Robinson
M.B.
(
2007
)
N-methyl-D-aspartate receptor-dependent regulation of the glutamate transporter excitatory amino acid carrier 1
.
J. Biol. Chem.
282
,
17594
17607
87
Zhao
L.
,
Li
H.
,
Guo
R.
,
Ma
T.
,
Hou
R.
,
Ma
X.
et al
(
2013
)
miR-137, a new target for post-stroke depression?
Neural Regen. Res.
8
,
2441
88
Ross
C.A.
,
Margolis
R.L.
,
Reading
S.A.
,
Pletnikov
M.
and
Coyle
J.T.
(
2006
)
Neurobiology of schizophrenia
.
Neuron
52
,
139
153
89
DeVito
L.M.
,
Balu
D.T.
,
Kanter
B.R.
,
Lykken
C.
,
Basu
A.C.
,
Coyle
J.T.
et al
(
2011
)
Serine racemase deletion disrupts memory for order and alters cortical dendritic morphology
.
Genes, Brain and Behavior
10
,
210
222
90
Buchanan
R.W.
,
Javitt
D.C.
,
Marder
S.R.
,
Schooler
N.R.
,
Gold
J.M.
,
McMahon
R.P.
et al
(
2007
)
The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments
.
Am. J. Psychiatry
164
,
1593
1602
91
Du Bois
T.M.
and
Huang
X.F.
(
2007
)
Early brain development disruption from NMDA receptor hypofunction: relevance to schizophrenia
.
Brain Res. Rev.
53
,
260
270
92
Miller
B.H.
,
Zeier
Z.
,
Xi
L.
,
Lanz
T.A.
,
Deng
S.
,
Strathmann
J.
et al
(
2012
)
MicroRNA-132 dysregulation in schizophrenia has implications for both neurodevelopment and adult brain function
.
Proc. Natl. Acad. Sci. U.S.A.
109
,
3125
3130
93
Kim
A.H.
,
Reimers
M.
,
Maher
B.
,
Williamson
V.
,
McMichael
O.
,
McClay
J.L.
et al
(
2010
)
MicroRNA expression profiling in the prefrontal cortex of individuals affected with schizophrenia and bipolar disorders
.
Schizophr. Res.
124
,
183
191
94
Zhang
Y.
,
Fan
M.
,
Wang
Q.
,
He
G.
,
Fu
Y.
,
Li
H.
et al
(
2015
)
Polymorphisms in microRNA genes and genes involving in NMDAR signaling and schizophrenia: a case-control study in Chinese han population
.
Sci. Rep.
5
,
12984
95
Heresco-Levy
U.
and
Javitt
D.C.
(
1998
)
The role of N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission in the pathophysiology and therapeutics of psychiatric syndromes
.
Eur. Neuropsychopharmacol.
8
,
141
152
96
Beveridge
N.J.
,
Gardiner
E.
,
Carroll
A.P.
,
Tooney
P.A.
and
Cairns
M.J.
(
2010
)
Schizophrenia is associated with an increase in cortical microRNA biogenesis
.
Mol. Psychiatry
15
,
1176
1189
97
Muddashetty
R.S.
,
Nalavadi
V.C.
,
Gross
C.
,
Yao
X.
,
Xing
L.
,
Laur
O.
et al
(
2011
)
Reversible inhibition of PSD-95 mRNA translation by miR-125a, FMRP phosphorylation, and mGluR signaling
.
Mol. Cell
42
,
673
688
98
Zhang
Y.L.
,
Xing
R.Z.
,
Luo
X.B.
,
Xu
H.
,
Chang
R.C.
,
Zou
L.Y.
et al
(
2016
)
Anxiety-like behavior and dysregulation of miR-34a in triple transgenic mice of Alzheimer's disease
.
Eur. Rev. Med. Pharmacol. Sci.
20
,
2853
2862
99
Long
J.M.
,
Ray
B.
and
Lahiri
D.K.
(
2012
)
MicroRNA-153 physiologically inhibits expression of amyloid-β precursor protein in cultured human fetal brain cells and is dysregulated in a subset of Alzheimer disease patients
.
J. Biol. Chem.
287
,
31298
31310
100
Willemsen
M.H.
,
Vallès
A.
,
Kirkels
L.A.
,
Mastebroek
M.
,
Loohuis
N.O.
,
Kos
A.
et al
(
2011
)
Chromosome 1p21. 3 microdeletions comprising DPYD and MIR137 are associated with intellectual disability
.
J. Med. Genet.
48
,
810
818
101
Geekiyanage
H.
,
Jicha
G.A.
,
Nelson
P.T.
and
Chan
C.
(
2012
)
Blood serum miRNA: non-invasive biomarkers for Alzheimer’s disease
.
Exp. Neurol.
235
,
491
496
102
Lin
S.L.
(
2015
)
microRNAs and fragile X syndrome
. In
microRNA: Medical Evidence
, pp.
107
121
,
Springer International Publishing
103
Chen
H.P.
,
Zhou
W.
,
Kang
L.M.
,
Yan
H.
,
Zhang
L.
,
Xu
B.H.
et al
(
2014
)
Intrathecal miR-96 inhibits Nav1. 3 expression and alleviates neuropathic pain in rat following chronic construction injury
.
Neurochem. Res.
39
,
76
83
104
Yu
B.
,
Qian
T.
,
Wang
Y.
,
Zhou
S.
,
Ding
G.
,
Ding
F.
et al
(
2012
)
miR-182 inhibits Schwann cell proliferation and migration by targeting FGF9 and NTM, respectively at an early stage following sciatic nerve injury
.
Nucleic Acids Res.
40
,
10356
10365
105
Gong
K.
,
Kung
L.H.
,
Magni
G.
,
Bhargava
A.
and
Jasmin
L.
(
2014
)
Increased response to glutamate in small diameter dorsal root ganglion neurons after sciatic nerve injury
.
PLoS ONE
9
,
e95491
106
Zhou
H.Y.
,
Chen
S.R.
and
Pan
H.L.
(
2011
)
Targeting N-methyl-D-aspartate receptors for treatment of neuropathic pain
.
Exp. Rev. Clin. Pharmacol.
4
,
379
388
107
Sempere
L.F.
,
Freemantle
S.
,
Pitha-Rowe
I.
,
Moss
E.
,
Dmitrovsky
E.
and
Ambros
V.
(
2004
)
Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation
.
Genome Biol.
5
,
R13