Upregulation of miR-19b-3p exacerbates chronic stress-induced changes in synaptic plasticity and cognition by targeting Drebrin

Chen, Jingli; Liu, Chang; Mu, X. S.; Zhu, Junquan

doi:10.1016/j.neuropharm.2022.108951

Cited by 7 publications

(3 citation statements)

References 51 publications

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“…p < 0.05) for the microRNA miR-19b-3p term in addition to the Spg33-Rtn complex ( Figure 4C ), suggesting this miRNA may have altered neuron-specific (i.e., in both excitatory and inhibitory) activity in Setbp1 S858R compared to control. Previous studies have shown in mouse hippocampal neurons that miR-19b-3p is more highly expressed under chronic restraint stress 35 than controls, and changes in AS with genes associated with this microRNA may indicate a neuronal stress response. We also identified terms from significant SJU genes for pathways and miRNAs in astrocytes, OPCs, and vascular cells (n = 3, 1, 1, Fisher’s exact test, adj.…”

Section: Resultsmentioning

confidence: 94%

Cell-type-specific alternative splicing in the cerebral cortex of a Schinzel-Giedion Syndrome patient variant mouse model

Jones,

Howton,

Soelter

et al. 2024

Preprint

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Schinzel-Giedion Syndrome (SGS) is an ultra-rare Mendelian disorder caused by gain-of-function mutations in theSETBP1gene. While previous studies determined multiple roles for howSETBP1and associated pathways may cause disease manifestation, they have not assessed whether cell-type-specific alternative splicing (AS) plays a role in SGS. We used STARsolo to quantify gene and splice junction (SJ) expression for 51,465 nuclei previously generated from the cerebral cortex of atypicalSetbp1S858RSGS patient variant mice (n = 3) and wild-type control mice (n = 3). After cell type annotation, we performed pseudobulk differential gene expression and SJ usage (SJU) analyses across cell types and conditions. We identified 34 genes with statistically significant alterations in SJU. Oligodendrocytes had the most genes with changes in SJU, followed by astrocytes, excitatory, and inhibitory neurons. One gene,Son, a splicing cofactor known to cause the neurodevelopmental disorder ZTTK Syndrome, had SJU changes in all six non-vascular cell types we measured inSetbp1S858Rcompared to controls. This is the first research to report AS changes in the cerebral cortex of an SGS model and the first study to link SGS to perturbations inSon.

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Section: Resultsmentioning

confidence: 94%

Cell-type-specific alternative splicing in the cerebral cortex of a Schinzel-Giedion Syndrome patient variant mouse model

Jones,

Howton,

Soelter

et al. 2024

Preprint

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“…To further characterize the antidepressant effects of engelitin, we employed CRS, which is currently regarded as one of the most predictive animal models of depression 18,19 . No substantial alterations were observed in each group's mice body weight before the experiment; however, after inducing CRS, the weight of mice in differrent groups altered (Figure 3B).…”

Section: Resultsmentioning

confidence: 99%

Engeletin alleviates depression‐like phenotype by increasing synaptic plasticity via the BDNF‐TrkB‐mTORC1 signalling pathway

Xu,

Zhang,

et al. 2023

J Cellular Molecular Medi

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Major depressive disorder (MDD) is a severe mental disorder associated with high rates of morbidity and mortality. Current first‐line pharmacotherapies for MDD are based on enhancement of monoaminergic neurotransmission, but these antidepressants are still insufficient and produce significant side‐effects. Consequently, the development of novel antidepressants and therapeutic targets is desired. Engeletin, a natural Smilax glabra rhizomilax derivative, is a compound with proven efficacy in treating ischemic stroke, yet its therapeutic effects and mechanisms for depression remain unexplored. The effects of engeletin were assessed in the forced swimming test (FST) and tail suspension test (TST) in mice. Engeletin was also investigated in the chronic restraint stress (CRS) mouse model of depression with fluoxetine (FLX) as the positive control. Changes in prefrontal cortex (PFC) spine density, synaptic plasticity‐linked protein expressions and the brain‐derived neurotrophic factor (BDNF)‐tyrosine kinase B (TrkB)‐ mammalian target of rapamycin complex 1 (mTORC1) signalling pathway after chronic stress and engeletin treatment were then investigated. The TrkB and mTORC1 selective inhibitors, ANA‐12 and rapamycin, respectively, were utilized to assess the engeletin's antidepressive mechanisms. Our data shows that engeletin exhibited antidepressant‐like activity in the FST and TST in mice without affecting locomotor activity. Furthermore, it exhibited efficiency against the depression of CRS model. Moreover, it enhanced the BDNF‐TrkB‐mTORC1 pathway in the PFC during CRS and altered the reduction in dendritic spine density and levels of synaptic plasticity‐linked protein induced by CRS. In conclusion, engeletin has antidepressant activity via activation of the BDNF‐TrkB‐mTORC1 signalling pathway and upregulation of PFC synaptic plasticity.

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“…In chronic restraint stress mice, silencing miR-19b-3p expression in vivo or in vitro with an inhibitor increases Drebrin expression, improves the abnormal dendritic structure, and increases spine density in hippocampal CA1 pyramidal neurons ( Table 1 ). By targeting Drebrin, miR-19b-3p upregulation exacerbates chronic restraint stress-induced abnormal synaptic plasticity and cognitive impairment [ 28 ].…”

Section: Resultsmentioning

confidence: 99%

MAPK Is a Mutual Pathway Targeted by Anxiety-Related miRNAs, and E2F5 Is a Putative Target for Anxiolytic miRNAs

et al. 2023

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Anxiety-related disorders (ARDs) are chronic neuropsychological diseases and the sixth leading cause of disability in the world. As dysregulation of microRNAs (miRs) are observed in the pathological course of neuropsychiatric disorders, the present study aimed to introduce miRs that underlie anxiety processing in the brain. First, we collected the experimentally confirmed anxiety-related miRNAs (ARmiRs), predicted their target transcripts, and introduced critical cellular pathways with key commune hub genes. As a result, we have found nine anxiolytic and ten anxiogenic ARmiRs. The anxiolytic miRs frequently target the mRNA of Acyl-CoA synthetase long-chain family member 4 (Acsl4), AFF4-AF4/FMR2 family member 4 (Aff4), and Krüppel like transcription factor 4 (Klf4) genes, where miR-34b-5p and miR-34c-5p interact with all of them. Moreover, the anxiogenic miRs frequently target the mRNA of nine genes; among them, only two miR (miR-142-5p and miR-218-5p) have no interaction with the mRNA of trinucleotide repeat-containing adaptor 6B (Tnrc6b), and miR-124-3p interacts with all of them where MAPK is the main signaling pathway affected by both anxiolytic and anxiogenic miR. In addition, the anxiolytic miR commonly target E2F transcription factor 5 (E2F5) in the TGF-β signaling pathway, and the anxiogenic miR commonly target Ataxin 1 (Atxn1), WASP-like actin nucleation promoting factor (Wasl), and Solute Carrier Family 17 Member 6 (Slc17a6) genes in the notch signaling, adherence junction, and synaptic vesicle cycle pathways, respectively. Taken together, we conclude that the most important anxiolytic (miR-34c, Let-7d, and miR-17) and anxiogenic (miR-19b, miR-92a, and 218) miR, as hub epigenetic modulators, potentially influence the pathophysiology of anxiety, primarily via interaction with the MAPK signaling pathway. Moreover, the role of E2F5 as a novel putative target for anxiolytic miRNAs in ARDs disorders deserves further exploration.

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Upregulation of miR-19b-3p exacerbates chronic stress-induced changes in synaptic plasticity and cognition by targeting Drebrin

Cited by 7 publications

References 51 publications

Cell-type-specific alternative splicing in the cerebral cortex of a Schinzel-Giedion Syndrome patient variant mouse model

Cell-type-specific alternative splicing in the cerebral cortex of a Schinzel-Giedion Syndrome patient variant mouse model

Engeletin alleviates depression‐like phenotype by increasing synaptic plasticity via the BDNF‐TrkB‐mTORC1 signalling pathway

MAPK Is a Mutual Pathway Targeted by Anxiety-Related miRNAs, and E2F5 Is a Putative Target for Anxiolytic miRNAs

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