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Local regulation of dendritic GluA1 by miR-501-3p. In A and B, primary neurons were treated with NMDA (30 µM for 5 min) and collected at 90 min after treatment to test for miR-501-3p. (A) The level of miR-501-3p in whole cell lysates; n = 3–5 experiments. (B) miR-501-3p associated with RISC; n = 3–4 experiments. In C and D, transfected hippocampal neurons (17 DIV; 3 d after transfection) were treated with NMDA, and then stained for GluA1. (C) Representative images of transfected neurons. (D) Quantification of C; n = 14–29 cells for each group; AP5 was added 10 min before treatment and present during and after NMDA treatment. In E–G, hippocampal slices in which cell bodies of CA1 pyramidal neurons were removed or intact hippocampal slices were treated with NMDA (30 µM for 5 min). (E) Representative immunoblots. (F) Quantification of E; n = 4 rats for the intact slice group and 6 rats for the neuropil group. (G) miR-501-3p expression normalized to U6; n = 5 rats for the intact slice group and 6 rats for the neuropil group. Data are presented as mean ± SEM; Mann-Whitney U test is used for statistical analysis; *, P < 0.05; **, P < 0.01; ***, P < 0.005. Bar, 5 µm.
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The number of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in synapses determines synaptic strength. AMPAR expression can be regulated locally in dendrites by synaptic activity. The mechanisms of activity-dependent local regulation of AMPAR expression, however, remain unclear. Here, we tested whether microRNAs (miRNAs) ar...
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Citations
... The co-existence of pre-miRNAs and Dicer in these areas implies a mechanism that ensures miRNA specificity and rapid conversion to mature forms as required [55,56]. Emerging research further hints that synapses may actively participate in transforming precursor miRNAs into mature forms, possibly influenced by NMDA receptor activity [52,57,58]. A hypothesis that synaptic activation might be instrumental in this conversion process has been proposed [59,60], though it requires further exploration. ...
Depression is a major contributor to the overall global burden of disease. The discovery of biomarkers for diagnosis or prediction of treatment responses and as therapeutic agents is a current priority. Previous studies have demonstrated the importance of short RNA molecules in the etiology of depression. The most extensively researched of these are microRNAs, a major component of cellular gene regulation and function. MicroRNAs function in a temporal and tissue-specific manner to regulate and modify the post-transcriptional expression of target mRNAs. They can also be shuttled as cargo of extracellular vesicles between the brain and the blood, thus informing about relevant mechanisms in the CNS through the periphery. In fact, studies have already shown that microRNAs identified peripherally are dysregulated in the pathological phenotypes seen in depression. Our article aims to review the existing evidence on microRNA dysregulation in depression and to summarize and evaluate the growing body of evidence for the use of microRNAs as a target for diagnostics and RNA-based therapies.
... Numerous specific miRNAs are essential for long-term neuronal plasticity and consequent memory formation by regulating the translation of key synaptic proteins 8,11,12 . We and others have shown previously that the NMDAR-dependent activation of miRNA-dependent gene silencing is required to modulate the expression of proteins that regulate the actin cytoskeleton or membrane trafficking processes to cause changes in spine morphology and induce LTD [13][14][15][16] . ...
... Depletion of specific miRNAs blocks plasticity expressed just a few minutes after stimulation and blocks the formation of memories that take a similarly short period of training, indicating that miRNA systems are critical for such rapid plasticity 14,[17][18][19] . While NMDAR stimulation regulates the transcription of miRNA genes, it takes 1 h following stimulus to reach a significant increase in mature miRNA 14,15 . Furthermore, individual miRNAs typically target several different mRNAs 10,20 ; therefore, increasing transcription of an individual miRNA does not provide the necessary silencing specificity on its own. ...
... Considering each of these in turn, while it has been shown that miRNA gene transcription is regulated by NMDAR stimulation 14,15 , for processes where miRNA-dependent silencing is required within a few minutes of the stimulus, transcriptional control is not fast enough. This is especially the case in neurons where the location of the stimulus, and of the consequent silencing, may be far from the cell nucleus and would rely on long-distance RNA transport along dendrites. ...
MicroRNAs (miRNAs) repress translation of target mRNAs by associating with Argonaute (Ago) proteins in the RNA-induced silencing complex (RISC) to modulate protein expression. Specific miRNAs are required for NMDA receptor (NMDAR)-dependent synaptic plasticity by repressing the translation of proteins involved in dendritic spine morphogenesis. Rapid NMDAR-dependent silencing of Limk1 is essential for spine shrinkage and requires Ago2 phosphorylation at S387. Not all gene silencing events are modulated by S387 phosphorylation, and the mechanisms that govern the selection of specific mRNAs for silencing downstream of S387 phosphorylation are unknown. Here, we show that NMDAR-dependent S387 phosphorylation causes a rapid and transient increase in the association of Ago2 with Limk1, but not Apt1 mRNA. The specific increase in Limk1 mRNA binding to Ago2 requires recruitment of the helicase DDX6 to RISC. Furthermore, we show that DDX6 is required for NMDAR-dependent silencing of Limk1 via miR-134, but not Apt1 via miR-138, and is essential for NMDAR-dependent spine shrinkage. This work defines a novel mechanism for the rapid transduction of NMDAR stimulation into miRNA-mediated translational repression of specific genes to control dendritic spine morphology.
... (b) ROC curve based on the predicted probability of logistic regression for Models 1 and 2 in Table 4. AUC, area under the curve; MCI, mild cognitive impairment; non-DM, nondiabetes mellitus. the Gria1 gene, one of the subunits of AMPARs (Hu et al., 2015). ...
Tight junction disruption and dysfunction are involved in the progression of blood–brain barrier (BBB) breakdown. Recent investigations have revealed BBB disruption in patients with vascular cognitive decline. Our previous studies showed that miR‐501‐3p negatively regulates cerebral endothelial tight junction protein‐1, resulting in the disruption of the BBB, and playing an important role in the development of vascular cognitive impairment. BBB breakdown in white matter lesions is often seen in the patients with vascular mild cognitive impairment (MCI). We therefore hypothesize that most early‐phase MCI patients may demonstrate elevated expression of miR‐501‐3p and sought to investigate whether serum exosome miR‐501‐3p levels could be a clinical indicator for detecting mild cognitive impairment. One hundred and seventy‐eight subjects (aged 73 [68–75] years, 53% male) were recruited for this study. The Japanese version of the Montreal Cognitive Assessment (MoCA‐J) was used for detecting MCI. Serum exosome miR‐501‐3p expression levels were measured by qPCR methods. Patients were divided into two groups depending on whether their miR‐501‐3p ∆Ct values were above (“High”; n = 74) or below (“Low”; n = 104) cutoff levels determined by ROC curve. MCI was detected significantly more often in the miR‐501‐3p‐High group (vs. ‐Low group, 63.5% vs. 47.1%, respectively; p < 0.05). Multivariate logistic regression analysis showed a significant association between MCI status and High miR‐501‐3p (odds ratio 2.662; p < 0.01), improved vs. known risk factors. In non‐diabetic patients, High miR‐501‐3p was positively associated with MCI status (odds ratio 3.633; p < 0.01) and also positively associated with MCI status in those with atherosclerosis (odds ratio 3.219; p < 0.01). The present study demonstrates that elevated expression of blood exosomal miR‐501‐3p can indicate the presence of MCI in human patients. Early detection of vascular injuries may allow a reduction in progressive dementia through the management of vascular risk factors. image
... Among miRNAs, miR-137 has been linked to alcohol-related disorder in adolescent rats submitted to alcohol intermittent exposure (AIE) (Kyzar et al., 2019). Importantly, AMPA receptor subunit GluA1 is a direct target of miR-137 and miR-501-3p (Olde Loohuis et al., 2015); (Hu et al., 2015). Indeed, postsynaptic downregulation of miR-137 at CA3-CA1 hippocampal synapse selectively enhances AMPAR-mediated synaptic transmission, a mechanism mediated by metabotropic glutamate receptor 5 (mGlu5) (Olde Loohuis et al., 2015). ...
... Indeed, postsynaptic downregulation of miR-137 at CA3-CA1 hippocampal synapse selectively enhances AMPAR-mediated synaptic transmission, a mechanism mediated by metabotropic glutamate receptor 5 (mGlu5) (Olde Loohuis et al., 2015). In addition, miR-501-3p mediates the activity-dependent regulation of GluA1 expression (Hu et al., 2015). These data suggest that alcohol exposure during hippocampal development may impact the homeostasis of the glutamatergic synapse from a molecular, structural and functional point of view. ...
... In addition, the regulation of AMPA in disorders such as Alzheimer's disease, dementia, ischemia or schizophrenia, is dependent on MiR-181a, mir-30b, miR-124 and miR-223 (Ansai et al., 2019); (Hsu et al., 2019); (Gascon et al., 2014); (Harraz et al., 2014); (Amoah et al., 2020). Recently, it was reported that AMPAR subunit GluA1 is specifically targeted by miR-137 and miR-501-3p (Olde Loohuis et al., 2015); (Hu et al., 2015). Olde-Loouis and colleagues have shown that experimental up-or down-regulation of miR-137 parallels changes in GluA1 expression and that its postsynaptic downregulation selectively enhances AMPAR-mediated Table 1 Effect of EtOH on the expression of glutamatergic makers in the homogenate of immature hippocampal slices, expressed as mean % ± SEM. ...
Prenatal alcohol exposure (PAE) affects neuronal networks and brain development causing a range of physical, cognitive and behavioural disorders in newborns that persist into adulthood. The array of consequences associated with PAE can be grouped under the umbrella-term 'fetal alcohol spectrum disorders' (FASD). Unfortunately, there is no cure for FASD as the molecular mechanisms underlying this pathology are still unknown. We have recently demonstrated that chronic EtOH exposure, followed by withdrawal, induces a significant decrease in AMPA receptor (AMPAR) expression and function in developing hippocampus in vitro. Here, we explored the EtOH-dependent pathways leading to hippocampal AMPAR suppression. Organotypic hippocampal slices (2 days in cultures) were exposed to EtOH (150 mM) for 7 days followed by 24 h EtOH withdrawal. Then, the slices were analysed by means of RT-PCR for miRNA content, western blotting for AMPA and NMDA related-synaptic proteins expression in postsynaptic compartment and electrophysiology to record electrical properties from CA1 pyramidal neurons. We observed that EtOH induces a significant downregulation of postsynaptic AMPA and NMDA subunits and relative scaffolding protein expression and, accordingly, a decrease of AMPA-mediated neurotransmission. Simultaneously, we found that chronic EtOH induced-upregulation of miRNA 137 and 501-3p and decreased AMPA-mediated neurotransmission are prevented by application of the selective mGlu5 antagonist MPEP during EtOH withdrawal. Our data indicate mGlu5 via miRNA137 and 501-3p expression as key factors in the regulation of AMPAergic neurotransmission that may contribute, at least in part, to the pathogenesis of FASD.
... The paper also concludes inappropriate re-entry into the cell cycle leads to apoptotic cell death, which precedes the development of senile plaques and NFTs [81]. Hu et al. (2015) explains one of the mechanisms of miR-501-3p in synaptic function. α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are ionotropic glutamate receptors that determine the strengths of synapses. ...
... The miRNA then directly binds to the 3 UTR of Gria1, a gene that codes for the GluA1 subunit of AMPAR, and decreases GluA1 expression. The downregulation of GluA1 expression by miR-501-3p occurs locally in the dendrites and is vital for long-lasting spine remodeling [86]. As previously discussed, miR-501-3p was found to be upregulated in the brains of AD patients, and its expression increased as AD progressed. ...
MicroRNAs (miRNAs) are non-coding RNAs that play a major role in gene regulation in several diseases. MicroRNA-502-3p (MiR-502-3p) has been previously characterized in a variety of human diseases such as osteoporosis, diabetes, tuberculosis, cancers, and neurological disorders. Our studies recently explored the new role of miR-502-3p in regulating synapse function in Alzheimer’s disease (AD). AD is the most common cause of dementia in elderly individuals. Synapse is the initial target that is hit during AD progression. The most common causes of synapse dysfunction in AD are amyloid beta, hyperphosphorylated tau, and microglia activation. MiR-502-3p was found to be localized and overexpressed in the AD synapses. Overexpression of miR-502-3p was correlated with AD severity in terms of Braak stages. Studies have shown that miR-502-3p modulates the glutaminergic and GABAergic synapse function in AD. The current study’s emphasis is to discuss the in-depth roles of miR-502-3p in human diseases and AD and the future possibilities concerning miR-502-3p as a therapeutic for AD treatment.
... Both miR-223 and miR-539 regulate GluN2B expression in response to excitotoxicity [109,110]. In LTD, the elevation of miR-135 and miR-501-3p expression requires GluN2A activity, whereas a decrease in miR-191 expression is caused by the activation of GluN2B [111,112]. Furthermore, it was found that the expression of miR-23a-3p and miR-151-3p is increased after LTP induction in the dentate gyrus [113]. The lack of miR-218-2 modulates cognitive function by impairing LTP to affect hippocampal morphology and presynaptic neurotransmitter release [114] MiRNAs, including miR-92a, miR-137, miR-153, miR-501-3p, miR-124, and miRNA-186-5p, can also be involved in the regulation of synaptic AMPAR expression. ...
Postoperative neurocognitive disorder (PND) is a disease that frequently develops in older patients during the perioperative period. It seriously affects the quality of life of the affected patients. Despite advancements in understanding PND, this disorder’s mechanisms remain unclear, including pathophysiological processes such as central synaptic plasticity and function, neuroinflammation, excitotoxicity, and neurotrophic support. Growing evidence suggests that microenvironmental changes are major factors for PND induction in older individuals. Exosomes are carriers for transporting different bioactive molecules between nerve cells in the microenvironment and maintaining intercellular communication and tissue homeostasis. Studies have shown that exosomes and microRNAs (miRNAs) are involved in various physiological and pathological processes, including neural processes related to PND, such as neurogenesis and cell death, neuroprotection, and neurotrophy. This article reviews the effects of exosomes and miRNAs on the brain microenvironment in PND and has important implications to improve PND diagnosis, as well as to develop targeted therapy of this disorder.
... Recent findings that substantial correlation between blood and brains in miRNA expression (14) supported feasibility to probe the miRNAs related to neural function in the peripheral blood transcriptome. Given that many miRNAs target synaptic proteins or signaling proteins regulating synapses (6,7,(18)(19)(20), the implication of synaptic plasticity in cognition and the genetic association of miRNAs (such as miR-137) with schizophrenia raises the possibility that miRNAs contribute to the pathogenesis of schizophrenia through regulation of synaptic plasticity. However, this notion needs to be consolidated by more experiments testing the functions of risk miRNAs. ...
... Moreover, the presence of genetic variants in the mGluR5 gene associated with schizophrenia (25,26) and upregulated mGluR5 in the postmortem brain tissues of schizophrenia (27,28) indicate that alterations to mGluR5 signaling might contribute to cognitive dysfunction associated with schizophrenia. Several studies have demonstrated that miRNAs play regulatory roles in synaptic plasticity by directly targeting synaptic receptors or their downstream targets (6,7,(18)(19)(20). For example, miR-501-3p has been reported to mediate the activity-dependent regulation of the AMPAR subunit GluA1 and long-lasting remodeling of rat dendritic spines (20). ...
... Several studies have demonstrated that miRNAs play regulatory roles in synaptic plasticity by directly targeting synaptic receptors or their downstream targets (6,7,(18)(19)(20). For example, miR-501-3p has been reported to mediate the activity-dependent regulation of the AMPAR subunit GluA1 and long-lasting remodeling of rat dendritic spines (20). miR-501-3p was also reported to be linked to cognitive functioning in patients with Alzheimer's disease (AD), where its serum expression level is significantly down-regulated compared to controls (29), suggesting that it contributes to synaptic plasticity related to cognitive functions, including learning and memory (20). ...
Schizophrenia is a polygenetic disease, the heterogeneity of which is likely complicated by epigenetic modifications yet to be elucidated. Here, we performed transcriptomic analysis of peripheral blood RNA from monozygotic twins discordant for schizophrenia and identified a schizophrenia-associated down-regulated microRNA, miR-501-3p. We showed that the loss of miR-501-3p in germline knockout (KO) male mice resulted in dendritic structure defects, glutamatergic transmission enhancement, and sociability, memory, and sensorimotor gating disruptions, which were attenuated when miR-501 expression was conditionally restored in the nervous system. Combining the results of proteomic analyses with the known genes linked to schizophrenia revealed that metabotropic glutamate receptor 5 (mGluR5) was one of the miR-501-3p targets and was elevated in vivo upon loss of miR-501. Treatment with the mGluR5 negative allosteric modulator 3-2((-methyl-4-thiazolyl) ethynyl) pyridine or the N -methyl- d -aspartate receptor antagonist 2-amino-5-phosphonopentanoic acid ameliorated the deficits observed in Mir501 -KO mice. The epigenetic and pathophysiological mechanism that links miR-501-3p to the modulation of glutamatergic transmission provides etiological implications for schizophrenia.
... A study by Letellier et al. found that miR-92a in hippocampal neurons selectively bound to the 3 UTR of GluA1, a subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, to inhibit its translation [39]. It has also been shown that miR-137 [40,41] and miR-501-3p [42,43] target GluA1 to regulate AMPA receptor-mediated synaptic currents and the number of functional synapses. Morquette et al. found that miR-223 targeted the 3 UTR of GluA2 and NR2B mRNAs to reduce the levels of GluA2 and NR2B, inhibit NMDAinduced Ca 2+ influx in hippocampal neurons, and protect the brain from injury caused by Glu-induced neuronal hyperexcitation [44,45]. ...
Depression is a psychiatric disorder that presents with a persistent depressed mood as the main clinical feature and is accompanied by cognitive impairment. Changes in neuroplasticity and neurogenesis greatly affect depression. Without genetic changes, epigenetic mechanisms have been shown to function by regulating gene expression during the body’s adaptation to stress. Studies in recent years have shown that as important regulatory factors in epigenetic mechanisms, microRNAs (miRNAs) play important roles in the development and progression of depression through the regulation of protein expression. Herein, we review the mechanisms of miRNA-mediated neuroplasticity in depression and discus synaptic structural plasticity, synaptic functional plasticity, and neurogenesis. Furthermore, we found that miRNAs regulate neuroplasticity through several signalling pathways to affect cognitive functions. However, these pathways do not work independently. Therefore, we try to identify synergistic correlations between miRNAs and multiple signalling pathways to broaden the potential pathogenesis of depression. In addition, in the future, dual-function miRNAs (protection/injury) are promising candidate biomarkers for the diagnosis of depression, and their regulated genes can potentially be used as target genes for the treatment of depression.
... Mir-137 targets the Gria-UTR reducing the synthesis of GluA1 subunit leading to a reduction in synaptic strength. NMDAR dependent LTD has been linked to miRNAs, such as miR-501-3p, which are rapidly upregulated to control GluA1 expression in response to NMDAR activation, albeit after some delay (Hu et al., 2015). The delay, Dr. Hanley argues, suggests that miR-501-3p is unlikely to be involved in the early stages of LTD expression but rather in its maintenance. ...
Knowledge of the biology of ionotropic glutamate receptors (iGluRs) is a prerequisite for any student of the neurosciences. But yet, half a century ago, the situation was quite different. There was fierce debate on whether simple amino acids, such as L-glutamic acid (L-Glu), should even be considered as putative neurotransmitter candidates that drive excitatory synaptic signaling in the vertebrate brain. Organic chemist, Jeff Watkins, and physiologist, Dick Evans, were amongst the pioneering scientists who shed light on these tribulations. By combining their technical expertise, they performed foundational work that explained that the actions of L-Glu were, in fact, mediated by a family of ion-channels that they named NMDA-, AMPA- and kainate-selective iGluRs. To celebrate and reflect upon their seminal work, Neuropharmacology has commissioned a series of issues that are dedicated to each member of the Glutamate receptor superfamily that includes both ionotropic and metabotropic classes. This issue brings together nine timely reviews from researchers whose work has brought renewed focus on AMPA receptors (AMPARs), the predominant neurotransmitter receptor at central synapses. Together with the larger collection of papers on other GluR family members, these issues highlight that the excitement, passion, and clarity that Watkins and Evans brought to the study of iGluRs is unlikely to fade as we move into a new era on this most interesting of ion-channel families.
... Since glutamatergic neurotransmission plays a key role in synaptic function and synaptic plasticity processes, including long-term potentiation (LTP) and long-term depression (LTD), numerous studies of miRNAs' targets have been conducted on glutamate receptors and excitatory synapses in AD. It is suggested that miR-9, miR-92, miR-137, and miR-501 selectively regulate GluA1 trafficking, resulting in a reduction of the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid glutamate receptor (AMPAR) insertion in the cell surface [112][113][114][115]. Additionally, the increased miR-181a, by accumulation of Aβ, significantly decreased the GluA2 subunit in AMPAR and other plasticity-related protein expression (i.e., scaffolding proteins and post-synaptic density 95) in mouse hippocampi, which, in turn, causes memory deficits [116]. ...
Alzheimer’s disease (AD), an age-dependent, progressive neurodegenerative disorder, is the most common type of dementia, accounting for 50–70% of all dementia cases. Due to the increasing incidence and corresponding socioeconomic burden of dementia, it has rapidly emerged as a challenge to public health worldwide. The characteristics of AD include the development of extracellular amyloid-beta plaques and intracellular neurofibrillary tangles, vascular changes, neuronal inflammation, and progressive brain atrophy. However, the complexity of the biology of AD has hindered progress in elucidating the underlying pathophysiological mechanisms of AD, and the development of effective treatments. MicroRNAs (miRNAs, which are endogenous, noncoding RNAs of approximately 22 nucleotides that function as posttranscriptional regulators of various genes) are attracting attention as powerful tools for studying the mechanisms of diseases, as they are involved in several biological processes and diseases, including AD. AD is a multifactorial disease, and several reports have suggested that miRNAs play an important role in the pathological processes of AD. In this review, the basic biology of miRNAs is described, and the function and physiology of miRNAs in the pathological processes of AD are highlighted. In addition, the limitations of current pharmaceutical therapies for the treatment of AD and the development of miRNA-based next-generation therapies are discussed.
