Neurite-Enriched MicroRNA-218 Stimulates Translation of the GluA2 Subunit and Increases Excitatory Synaptic Strength

Rocchi, Anna; Moretti, Daniela; Lignani, Gabriele; Colombo, Elisabetta; Scholz‐Starke, Joachim; Baldelli, Pietro; Tkatch, Tatiana; Benfenati, Fabio

doi:10.1007/s12035-019-1492-7

Cited by 34 publications

(29 citation statements)

References 77 publications

(90 reference statements)

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“…This finding suggests that miR-218 in the mPFC facilitates the formation of thin dendritic spines on pyramidal neurons under stressful conditions, and that these changes in spine plasticity might be protective against the functional and behavioral alterations induced by chronic stress. This idea is supported by recent evidence showing that miR-218 is enriched in forebrain synaptosomes and neurites of primary cultured neurons 59, 60 and regulates excitatory synaptic transmission at both single neuron and network levels 60 .…”

Section: Discussionmentioning

confidence: 66%

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

et al. 2019

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Low miR-218 expression in the medial prefrontal cortex (mPFC) is a consistent trait of depression. Here we assessed whether miR-218 in the mPFC confers resilience or susceptibility to depression-like behaviors in adult mice, using the chronic social defeat stress (CSDS) model of depression. We also investigated whether stress-induced variations of miR-218 expression in the mPFC can be detected in blood. We find that downregulation of miR-218 in the mPFC increases susceptibility to a single session of social defeat, whereas overexpression of miR-218 selectively in mPFC pyramidal neurons promotes resilience to CSDS and prevents stress-induced morphological alterations to those neurons. After CSDS, susceptible mice have low levels of miR-218 in the blood as compared to control or resilient groups. We show further that up- and downregulation of miR-218 levels specifically in the mPFC correlates with miR-218 expression in blood. Our results suggest that miR-218 in the adult mPFC might function as a molecular switch that determines susceptibility versus resilience to chronic stress, and that stress-induced variations in mPFC levels of miR-218 could be detected in blood. We propose that blood expression of miR-218 might serve as potential readout of vulnerability to stress and as a proxy of mPFC function.

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Section: Discussionmentioning

confidence: 66%

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

et al. 2019

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“…Hippocampal neurons were stained as described 50 . The primary antibodies used were anti-Synapsin I (clone 10.22, Millipore, USA), anti-vesicular glutamate transporter-1 (VGLUT1, AB5905, Millipore), antivesicular GABA transporter (VGAT, 131 011, Synaptic System), anti-β-tubulin III (T2200, Sigma-Aldrich), antigreen fluorescent protein (GFP, 11814460001, Sigma-Aldrich), anti-FcγRII/III (clone 2.4G2, ABS410, Enzo LifeScience).…”

Section: Immunofluorescencementioning

confidence: 99%

Autoantibodies to synapsin I sequestrate synapsin I and alter synaptic function

et al. 2019

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Synapsin I is a phosphoprotein that coats the cytoplasmic side of synaptic vesicles and regulates their trafficking within nerve terminals. Autoantibodies against Syn I have been described in sera and cerebrospinal fluids of patients with numerous neurological diseases, including limbic encephalitis and clinically isolated syndrome; however, the effects and fate of autoantibodies in neurons are still unexplored. We found that in vitro exposure of primary hippocampal neurons to patient's autoantibodies to SynI decreased the density of excitatory and inhibitory synapses and impaired both glutamatergic and GABAergic synaptic transmission. These effects were reproduced with a purified SynI antibody and completely absent in SynI knockout neurons. Autoantibodies to SynI are internalized by FcγII/III-mediated endocytosis, interact with endogenous SynI, and promote its sequestration and intracellular aggregation. Neurons exposed to human autoantibodies to SynI display a reduced density of SVs, mimicking the SynI loss-of-function phenotype. Our data indicate that autoantibodies to intracellular antigens such as SynI can reach and inactivate their targets and suggest that an antibody-mediated synaptic dysfunction may contribute to the evolution and progression of autoimmune-mediated neurological diseases positive for SynI autoantibodies.

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“…Experimental manipulation of hippocampal activity was shown to inversely regulate miR-218 expression. Silencing of synaptic activity by tetrodotoxin increased miR-218 expression, whereas induction of sustained synaptic activity with the combination of the GABAA receptor antagonist bicuculline and the K + channel blocker 4-aminopyridine (BiC/4-AP) decreased miR-218 expression 73 . Future studies could be directed to assess levels of miR-133a and miR-218 as risk factors for epilepsy, and in epileptic patients as potential biomarkers for individual differences in response to levetiracetam.…”

Section: Discussionmentioning

confidence: 99%

Integration of postmortem amygdala expression profiling, GWAS, and functional cell culture assays: neuroticism-associated synaptic vesicle glycoprotein 2A (SV2A) gene is regulated by miR-133a and miR-218

et al. 2020

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Recent genome-wide studies have begun to identify gene variants, expression profiles, and regulators associated with neuroticism, anxiety disorders, and depression. We conducted a set of experimental cell culture studies of gene regulation by micro RNAs (miRNAs), based on genome-wide transcriptome, proteome, and miRNA expression data from twenty postmortem samples of lateral amygdala from donors with known neuroticism scores. Using Ingenuity Pathway Analysis and TargetScan, we identified a list of mRNA-protein-miRNA sets whose expression patterns were consistent with miRNA-based translational repression, as a function of trait anxiety. Here, we focused on one gene from that list, which is of particular translational significance in Psychiatry: synaptic vesicle glycoprotein 2A (SV2A) is the binding site of the anticonvulsant drug levetiracetam ((S)-α-Ethyl-2-oxo-1-pyrrolidineacetamide), which has shown promise in anxiety disorder treatments. We confirmed that SV2A is associated with neuroticism or anxiety using an original GWAS of a community cohort (N = 1,706), and cross-referencing a published GWAS of multiple cohorts (Ns ranging from 340,569 to 390,278). Postmortem amygdala expression profiling implicated three putative regulatory miRNAs to target SV2A: miR-133a, miR-138, and miR-218. Moving from association to experimental causal testing in cell culture, we used a luciferase assay to demonstrate that miR-133a and miR-218, but not miR-138, significantly decreased relative luciferase activity from the SV2A dual-luciferase construct. In human neuroblastoma cells, transfection with miR-133a and miR-218 reduced both endogenous SV2A mRNA and protein levels, confirming miRNA targeting of the SV2A gene. This study illustrates the utility of combining postmortem gene expression data with GWAS to guide experimental cell culture assays examining gene regulatory mechanisms that may contribute to complex human traits. Identifying specific molecular mechanisms of gene regulation may be useful for future clinical applications in anxiety disorders or other forms of psychopathology.

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Neurite-Enriched MicroRNA-218 Stimulates Translation of the GluA2 Subunit and Increases Excitatory Synaptic Strength

Cited by 34 publications

References 77 publications

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

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

Autoantibodies to synapsin I sequestrate synapsin I and alter synaptic function

Integration of postmortem amygdala expression profiling, GWAS, and functional cell culture assays: neuroticism-associated synaptic vesicle glycoprotein 2A (SV2A) gene is regulated by miR-133a and miR-218

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