A microRNA negative feedback loop downregulates vesicle transport and inhibits fear memory

Mathew, Rebecca; Tatarakis, Antonis; Rudenko, Andrii; Johnson-Venkatesh, Erin; Yang, Yunyun; Murphy, Elisabeth A.; Todd, Travis P.; Schepers, Scott T.; Siuti, Nertila; Martorell, Anthony J; Falls, William A.; Hammack, Sayamwong E.; Walsh, Christopher A.; Tsai, Li‐Huei; Umemori, Hisashi; Bouton, Mark E.; Moazed, Danesh

doi:10.7554/elife.22467

Cited by 30 publications

(24 citation statements)

References 107 publications

(121 reference statements)

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“…A previous study reported that miR-153 is a contextual fear-induced miRNA and affects fear memory by targeting the Snap25 and Vamp2 genes [23]. Here, we first reported that miR-153 is also a CBH-induced miRNA.…”

Section: Discussionmentioning

confidence: 62%

“…Multiple miRNAs have been previously reported to regulate synaptic fusion-related proteins at the mRNA level. For example, miR-153 regulates Snap25, Vamp2, Snca, Trak2, Bsn and Pclo genes at the mRNA level [23]; miR-137 inhibits complexin-1, Nsf and Syt1 in mouse model of schizophrenia [20]; miR-34c targets VAMP-2 [21] and miR-135a binds the complexin-1 and complexin-2 genes in the amygdala [22]. To identify which one of the above miRNAs is involved in the CBH induced downregulation of fusion-related proteins in the hippocampi of rats, we performed qRT-PCR test.…”

Section: Mir-153 Targets Snare Complex-related Genes and The Syt1 Genementioning

confidence: 99%

“…Previous studies have reported that microRNAs (miR-NAs) could regulate presynaptic plasticity by targeting various vesicle-related proteins. For example, miR-137 impaired vesicle release in a mouse model of schizophrenia [20]; miR-34c was reported mediate amyloid-beta (Aβ)-induced synaptic failure by targeting VAMP2 [21]; knockdown of miR-135a triggered an early stress response by disturbing presynaptic vesicle release [22]; miR-153 was found to be a contextual fear-induced miRNA in the dentate gyrus [23] and was reported to regulate vesicle release in zebrafish [24]. However, these studies did not analyze CBH-induced changes in miRNA levels or their function in presynaptic plasticity.…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA-153 impairs presynaptic plasticity by blocking vesicle release following chronic brain hypoperfusion

et al. 2020

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Background: Chronic brain hypoperfusion (CBH) is closely related to Alzheimer's disease (AD) and vascular dementia (VaD). Meanwhile, synaptic pathology plays a prominent role in the initial stage of AD and VaD. However, whether and how CBH impairs presynaptic plasticity is currently unclear. Methods: In the present study, we performed a battery of techniques, including primary neuronal culture, patch clamp, stereotaxic injection of the lentiviral vectors, morris water maze (MWM), dual luciferase reporter assay, FM1-43 fluorescence dye evaluation, qRT-PCR and western blot, to investigate the regulatory effect of miR-153 on hippocampal synaptic vesicle release both in vivo and in vitro. The CBH rat model was generated by bilateral common carotid artery ligation (2VO). Results: Compared to sham rats, 2VO rats presented decreased field excitatory postsynaptic potential (fEPSP) amplitude and increased paired-pulse ratios (PPRs) in the CA3-CA1 pathway, as well as significantly decreased expression of multiple vesicle fusion-related proteins, including SNAP-25, VAMP-2, syntaxin-1A and synaptotagmin-1, in the hippocampi. The levels of microRNA-153 (miR-153) were upregulated in the hippocampi of rats following 2VO surgery, and in the plasma of dementia patients. The expression of the vesicle fusion-related proteins affected by 2VO was inhibited by miR-153, elevated by miR-153 inhibition, and unchanged by binding-site mutation or miR masks. FM1-43 fluorescence images showed that miR-153 blunted vesicle exocytosis, but this effect was prevented by either 2′-O-methyl antisense oligoribonucleotides to miR-153 (AMO-153) and miR-masking of the miR-153 binding site in the 3′ untranslated region (3'UTR) of the Snap25, Vamp2, Stx1a and Syt1 genes. Overexpression of miR-153 by lentiviral vector-mediated miR-153 mimics (lenti-pre-miR-153) decreased the fEPSP amplitude and elevated the PPR in the rat hippocampus, whereas overexpression of the antisense molecule (lenti-AMO-153) reversed these changes triggered by 2VO. Furthermore, lenti-AMO-153 attenuated the cognitive decline of 2VO rats.

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Section: Discussionmentioning

confidence: 62%

Section: Mir-153 Targets Snare Complex-related Genes and The Syt1 Genementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MicroRNA-153 impairs presynaptic plasticity by blocking vesicle release following chronic brain hypoperfusion

et al. 2020

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“…The 17th ranked gene was PTPRN2, and there appears to be a short unannotated transcript in NSCs ( Fig.7(e)). Notably, in mouse, an alternative promoter exists downstream of Ptprn2, and the transcription from the promoter drives the miR-153 precursor transcript embedded in the Ptprn2 gene region [36]. Moreover, miR-153 is highly expressed in mouse neural stem/progenitor cells (NSPCs), and the repression of miR-153 leads to differentiation, and hence, miR-153 modulates NSPCs [37].…”

Section: Hnsc-nc Datasetmentioning

confidence: 99%

A NMF-based approach to discover overlooked differentially expressed gene regions from single-cell RNA-seq data

Matsumoto

Hayashi

Ozaki

et al. 2019

Preprint

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Single-cell RNA sequencing has enabled researchers to quantify the transcriptomes of individual cells, infer cell types, and investigate differential expression among cell types, which will lead to a better understanding of the regulatory mechanisms of cell states. Transcript diversity caused by phenomena such as aberrant splicing events have been revealed, and differential expression of previously unannotated transcripts might be overlooked by annotation-based analyses. Accordingly, we have developed an approach to discover overlooked differentially expressed (DE) gene regions that complements annotation-based methods. We applied our algorithm to two datasets and discovered several intriguing DE transcripts, including a transcript related to the modulation of neural stem/progenitor cell differentiation.

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“…Indeed, expression of miRNA biogenesis regulators Dicer and Pasha (Dgcr8) impacts fear memories (10,11). Both cued and contextual fear conditioning (FC) regulate miRNA expression and modulation of such miRNAs impacts consolidation and retrieval (12)(13)(14)(15)(16)(17).…”

mentioning

confidence: 99%

microRNA regulation of persistent stress-enhanced memory

Sillivan

Jamieson

Nijs

et al. 2018

Preprint

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Disruption of persistent, stress-associated memories is relevant for treating posttraumatic stress disorder (PTSD) and related syndromes, which develop in a subset of individuals following a traumatic event. Using a stress-enhanced fear learning protocol that results in differential susceptibility in inbred mice, we integrated small-RNA sequencing with quantitative proteomics on basolateral amygdala tissue collected one month after training. We identified persistently changed microRNAs, including mir-135b-5p, and predicted target proteins associated with PTSD-like heightened fear expression. Functional manipulations of mir-135b-5p bidirectionally modulated stress-associated memory. mir-135b-5p is expressed in human amygdala and its passenger strand was elevated in serum from a well-characterized military PTSD cohort. miR-135b-5p is a therapeutic target for dampening persistent, stress-enhanced memory and its passenger strand a potential biomarker for responsivity to a mir-135-based therapeutic.One Sentence Summary: mir-135 can be manipulated to weaken persistent, stress-associated memory and serve as a biomarker of PTSD.Main Text: Unlike memory acquisition and consolidation, mechanisms supporting long-lasting, remote memory are largely unknown, yet highly relevant to neuropsychiatric disorders of memory, such as posttraumatic stress disorder (PTSD). PTSD is a chronic, debilitating disorder in which patients exhibit memories of trauma that are heightened, perseverant and extinctionresistant (1). Nearly everyone experiences at least one traumatic event in their lifetime, but only 10-20% will later display enduring symptoms of PTSD (2). Exposure therapy, a form of cognitive behavioral therapy (CBT) that utilizes extinction of fearful memories, is considered the gold standard PTSD treatment. However, some patients are resistant or experience exacerbated symptoms and, of those who do respond, most retain their PTSD diagnosis (3). Development of adjunctive pharmacotherapies to enhance success of CBT is needed, but deeper insight into the neurobiology of PTSD-like behaviors to identify potential targets is first required. To identify mechanisms governing differential stress susceptibility, we developed a stress-enhanced fear learning (SEFL) paradigm in inbred C57BL/6 mice that results in PTSD-like characteristics,

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A microRNA negative feedback loop downregulates vesicle transport and inhibits fear memory

Cited by 30 publications

References 107 publications

MicroRNA-153 impairs presynaptic plasticity by blocking vesicle release following chronic brain hypoperfusion

MicroRNA-153 impairs presynaptic plasticity by blocking vesicle release following chronic brain hypoperfusion

A NMF-based approach to discover overlooked differentially expressed gene regions from single-cell RNA-seq data

microRNA regulation of persistent stress-enhanced memory

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