MiR-218: a molecular switch and potential biomarker of susceptibility to stress

Torres‐Berrío, Angélica; Nouel, Dominique; Cuesta, Santiago; Parise, Eric M.; Restrepo-Lozano, José Maria; Larochelle, Pier; Nestler, Eric J.; Flores, Cecilia

doi:10.1038/s41380-019-0421-5

Cited by 59 publications

(65 citation statements)

References 59 publications

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“…Following these 5 min of physical interaction, the experimental mouse went through a 20 min session of sensory stress. Subthreshold social defeat sessions during a novel CD-1 aggressors' home cage was repeated daily for 3 days 21,22 . Once they weren't located in aggressors' cages, SSDS mice were singly housed in standard cages, and this protocol didn't result in social avoidance behaviour.…”

Section: Ssds Experimentsmentioning

confidence: 99%

Nedd4l downregulation of NRG1 in the mPFC induces depression-like behaviour in CSDS mice

Guo

Liu

et al. 2020

Transl Psychiatry

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The occurrence of major depressive disorders has been closely related to the vulnerability of stress. The medial prefrontal cortex (mPFC) is involved in regulating pathological reactivity to stress, changes in affective behaviour and cognitive functions by distress. Increasing evidence indicates that neuregulin 1 (NRG1) plays an important role in psychiatric illnesses, including depression, schizophrenia and bipolar disorder. However, whether NRG1 in the mPFC is related to stress vulnerability remains unclear. We here assessed the regulation of NRG1 by the E3 ubiquitin ligase Nedd4l (neural precursor cell expressed developmentally downregulated 4-like) and investigated whether NRG1 changes in the mPFC might lead to vulnerability to depression-like behaviours. We've identified a deficiency of NRG1 in the mPFC as a key factor that contributes to the regulation of stress susceptibility in mice, as further suggested by the finding that overexpression of NRG1 attenuated depression-like behaviours in the animal model of chronic social defeat stress (CSDS). Interestingly, RNA sequencing in the mPFC brain region showed no differences in NRG1 mRNA levels between control animals and stress-susceptible (SS) or resilient mice (RES) following CSDS. However, mRNA and protein levels of Nedd4l were markedly increased in SS mice, but not in RES mice compared to controls. Furthermore, ubiquitination of NRG1 was increased in SS mice. Remarkably, overexpression of Nedd4l in mouse mPFC induced a decrease in NRG1 level and caused vulnerability to stress by subthreshold social defeat stress (SSDS), while downregulation of Nedd4l expression in the mPFC rescued the vulnerability to stress-induced social avoidance and anhedonia. Our data strongly indicate that the Nedd4l-mediated downregulation of NRG1 acts as a critical role in depression-like phenotypes of mice in CSDS.

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Section: Ssds Experimentsmentioning

confidence: 99%

Nedd4l downregulation of NRG1 in the mPFC induces depression-like behaviour in CSDS mice

Guo

Liu

et al. 2020

Transl Psychiatry

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“…al. reported that miR218 in the blood of mice is produced in the mPFC (Torres-Berrio et al, 2019). Thus, it is plausible that miRs targeting BDNF are produced in the mPFC transported by blood, where they can target BDNF mRNA in megakaryocytes, for example (Chacon-Fernandez et al, 2016).…”

Section: Micrornas Targeting Bdnf Are Upregulated Only In Rapid Onsetmentioning

confidence: 99%

Differential Correlation of Serum BDNF and microRNA Content in Rats with Rapid or Late Onset of Heavy Alcohol Use

Ehinger

Phamluong

Darevesky

et al. 2019

Preprint

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Heavy alcohol use reduces the levels of the brain-derived neurotrophic factor (BDNF) in the prefrontal cortex of rodents through the upregulation of microRNAs targeting BDNF mRNA. In humans, an inverse correlation exists between circulating blood levels of BDNF and the severity of psychiatric disorders including alcohol abuse. Here, we set out to determine whether a history of heavy alcohol use produces comparable alterations in the blood of rats. We used an intermittent access to 20% alcohol using the 2-bottle choice paradigm (IA20%2BC), and measured circulating levels of BDNF protein and microRNAs in the serum of Long-Evans rats before and after 8-weeks of excessive alcohol intake. We observed that the drinking profile of heavy alcohol users is not unified; Whereas 70% of the rats gradually escalate their alcohol intake (Late Onset), 30% of alcohol users exhibit a very Rapid Onset of drinking (Rapid Onset). We found that serum BDNF levels are negatively correlated with alcohol intake in both Rapid Onset and Late Onset rats. In contrast, increased expression of the microRNAs (miRs) targeting BDNF, miR30a-5p, miR-195-5p, miR191-5p and miR206-3p, was detected only in the Rapid Onset rats. Finally, we report that the alcohol-dependent molecular changes are not due to alterations in platelet number. Our data suggest that rats exhibit both Late and Rapid Onset of alcohol intake. We further show that heavy alcohol use produces comparable changes in BDNF protein levels in both groups. However, circulating microRNAs are responsive to alcohol only in the Rapid Onset rats.

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“…In LTD, miRNA-191 decreased the elimination and contraction of DS by inhibiting TMOD2 (UniProt code Q9NZR1), a protein that promotes the depolymerization of actin (Hu et al, 2014). The miRNA-218 enhances the expression of GRIA2 subunit of AMPAR, increasing the amplitude of synaptic currents (Rocchi et al, 2019) and the formation of thin DS (Torres-Berrio et al, 2019).…”

Section: Regulation Dendritic Spines Plasticity By Mirnamentioning

confidence: 99%

Dendritic Spine and Synaptic Plasticity in Alzheimer’s Disease: A Focus on MicroRNA

Reza-Zaldívar¹,

Hernández-Sapiéns²,

Minjarez

et al. 2020

Front. Cell Dev. Biol.

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Dendrites and dendritic spines are dynamic structures with pivotal roles in brain connectivity and have been recognized as the locus of long-term synaptic plasticity related to cognitive processes such as learning and memory. In neurodegenerative diseases, the spine dynamic morphology alteration, such as shape and spine density, affects functional characteristics leading to synaptic dysfunction and cognitive impairment. Recent evidence implicates dendritic spine dysfunction as a critical feature in the pathogenesis of dementia, particularly Alzheimer's disease. The alteration of spine morphology and their loss is correlated with the cognitive decline in Alzheimer's disease patients even in the absence of neuronal loss, however, the underlying mechanisms are poorly understood. Currently, the microRNAs have emerged as essential regulators of synaptic plasticity. The changes in neuronal microRNA expression that contribute to the modification of synaptic function through the modulation of dendritic spine morphology or by regulating the local protein translation to synaptic transmission are determinant for synapse formation and synaptic plasticity. Focusing on microRNA and its targets may provide insight into new therapeutic opportunities. In this review we summarize the experimental evidence of the role that the microRNA plays in dendritic spine remodeling and synaptic plasticity and its potential therapeutic approach in Alzheimer's disease. Targeting synaptic deficits through the structural alteration of dendritic spines could form part of therapeutic strategies to improve synaptic plasticity and to ameliorate cognitive impairments in Alzheimer's disease and other neurological diseases.

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MiR-218: a molecular switch and potential biomarker of susceptibility to stress

Cited by 59 publications

References 59 publications

Nedd4l downregulation of NRG1 in the mPFC induces depression-like behaviour in CSDS mice

Nedd4l downregulation of NRG1 in the mPFC induces depression-like behaviour in CSDS mice

Differential Correlation of Serum BDNF and microRNA Content in Rats with Rapid or Late Onset of Heavy Alcohol Use

Dendritic Spine and Synaptic Plasticity in Alzheimer’s Disease: A Focus on MicroRNA

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