MicroRNA dysregulation in manic and euthymic patients with bipolar disorder

Camkurt, Mehmet Akif; Karababa, İbrahim Fatih; Kandemir, Sultan Basmacı; Fries, Gabriel R.; Bayazıt, Hüseyin; Ay, Mustafa; Kandemır, Hasan; Ay, Özlem İzci; Coşkun, Salih; Çiçek, Erdinç; Selek, Salih

doi:10.1016/j.jad.2019.09.060

Cited by 36 publications

(25 citation statements)

References 40 publications

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“…Levels of miR-125a were shown to be increased in FXS urine, consistent with previous observations showing the involvement of FMRP in the regulation of miR-125a expression. Altered peripheral miRNA levels have been detected in several neuropsychiatric disorders, including depression, schizophrenia, and ASD [48,49], and increased plasma miR-125a levels were very recently shown in patients with bipolar disorder and particularly in bipolar manic patients [50]. The results of the present study demonstrate the potential of urine miRNA profiling for miRNA biomarker development in FXS.…”

Section: Discussionsupporting

confidence: 61%

Urine microRNA Profiling Displays miR-125a Dysregulation in Children with Fragile X Syndrome

Putkonen

Laiho

Ethell³

et al. 2020

Cells

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A triplet repeat expansion leading to transcriptional silencing of the FMR1 gene results in fragile X syndrome (FXS), which is a common cause of inherited intellectual disability and autism. Phenotypic variation requires personalized treatment approaches and hampers clinical trials in FXS. We searched for microRNA (miRNA) biomarkers for FXS using deep sequencing of urine and identified 28 differentially regulated miRNAs when 219 reliably identified miRNAs were compared in dizygotic twin boys who shared the same environment, but one had an FXS full mutation, and the other carried a premutation allele. The largest increase was found in miR-125a in the FXS sample, and the miR-125a levels were increased in two independent sets of urine samples from a total of 19 FXS children. Urine miR-125a levels appeared to increase with age in control subjects, but varied widely in FXS subjects. Should the results be generalized, it could suggest that two FXS subgroups existed. Predicted gene targets of the differentially regulated miRNAs are involved in molecular pathways that regulate developmental processes, homeostasis, and neuronal function. Regulation of miR-125a has been associated with type I metabotropic glutamate receptor signaling (mGluR), which has been explored as a treatment target for FXS, reinforcing the possibility that urine miR-125a may provide a novel biomarker for FXS.

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Section: Discussionsupporting

confidence: 61%

Urine microRNA Profiling Displays miR-125a Dysregulation in Children with Fragile X Syndrome

Putkonen

Laiho

Ethell³

et al. 2020

Cells

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“…Instead, our work provide evidence that alternative miRNAs might might contribute to fine-tune DCC contents in a region-dependent manner. In this line, human studies have already implicated some of the miRNAs identified here such as miR-9-5p or let-7d-5p in psychiatric conditions (Camkurt et al, 2020;He et al, 2021;Maffioletti et al, 2016). Moreover, work in rodents have provided initial experimental evidences confirming such links (Bahi and Dreyer, 2018;Ma et al, 2019;Zhang et al, 2020).…”

Section: Discussionmentioning

confidence: 61%

Region-specific microRNA alterations in marmosets carrying SLC6A4 polymorphisms are associated with anxiety-like behavior

Popa

Bachar

Roberts

et al. 2021

Preprint

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Background: Neuroimaging studies have consistently reported that stress-related disorders such as depression and anxiety impinge on the activity of emotion regulation networks, namely in the ventromedial prefrontal cortex (vmPFC). This circuitry is known to be extensively modulated by serotonin and it has been long shown that genetic polymorphisms in the serotonin transporter gene (SLC6A4) are linked to anxiey and depression. vmPFC encompasses different brain regions in terms of cytoarchitecture, activity and connectivity. However, molecular heterogeneity within the vmPFC and how these differences affect emotional regulation and behavior have not been elucidated. Methods: Here, we took advantage of recently described polymorphisms in marmoset SLC6A4 gene linked to alter threat responses. Using FACS-sorted cells from different brain areas of genotyped marmosets, we tested the hypothesis that specific molecular changes in precise regions of the vmPFC underlie the behavioral differences and can be associated with high anxiety-like trait. Results: miRNA analysis of FACS-sorted cells from marmoset cortex revealed that clear miRNA profiles can be identified for different cell subsets (NeuN+ versus NeuN- cells) or cortical regions (visual cortex versus vmPFC). More importantly, marmosets bearing different SLC6A4 polymorphisms show distinct miRNAs signatures specifically in vmPFC area 32 neurons but not in the closely related vmPFC area 25 neurons. Finally, levels of these miRNAs were highly correlated to the anxiety-like score in a test of uncertain threat. Conclusions: These data demonstrate that molecular changes within area 32 likely underlie the differential anxiety-like responses associated with SLC6A4 polymorphisms.

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“…Other clinical implications include using miRNA expression profiles as molecular markers in BD and as predictors of treatment response. Furthermore, recent research has also shown phase-dependent miRNA dysregulation in BD patients, where greater miRNA dysregulation was seen in mania compared with euthymia (Camkurt et al, 2020). This provides an interesting avenue for further clinical research with regard to miRNA expression and different BD phases as well as the drugs used to treat those phases.…”

Section: Discussionmentioning

confidence: 99%

Drugs used to treat bipolar disorder act via microRNAs to regulate expression of genes involved in neurite outgrowth

et al. 2020

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Background: The drugs commonly used to treat bipolar disorder have limited efficacy and drug discovery is hampered by the paucity of knowledge of the pathophysiology of this disease. This study aims to explore the role of microRNAs in bipolar disorder and understand the molecular mechanisms of action of commonly used bipolar disorder drugs. Methods: The transcriptional effects of bipolar disorder drug combination (lithium, valproate, lamotrigine and quetiapine) in cultured human neuronal cells were studied using next generation sequencing. Differential expression of genes ( n=20) and microRNAs ( n=6) was assessed and the differentially expressed microRNAs were confirmed with TaqMan MicroRNA Assays. The expression of the differentially expressed microRNAs were inhibited to determine bipolar disorder drug effects on their target genes ( n=8). Independent samples t-test was used for normally distributed data and Kruskal-Wallis/Mann-Whitney U test was used for data not distributed normally. Significance levels were set at p<0.05. Results: We found that bipolar disorder drugs tended to increase the expression of miR-128 and miR-378 ( p<0.05). Putative target genes of these microRNAs targeted pathways including those identified as “neuron projection development” and “axonogenesis”. Many of the target genes are inhibitors of neurite outgrowth and neurogenesis and were downregulated following bipolar disorder drug combination treatment (all p<0.05). The bipolar disorder drug combination tended to decrease the expression of the target genes ( NOVA1, GRIN3A, and VIM), however this effect could be reversed by the application of microRNA inhibitors. Conclusions: We conclude that at a transcriptional level, bipolar disorder drugs affect several genes in concert that would increase neurite outgrowth and neurogenesis and hence neural plasticity, and that this effect is mediated (at least in part) by modulation of the expression of these two key microRNAs.

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MicroRNA dysregulation in manic and euthymic patients with bipolar disorder

Cited by 36 publications

References 40 publications

Urine microRNA Profiling Displays miR-125a Dysregulation in Children with Fragile X Syndrome

Urine microRNA Profiling Displays miR-125a Dysregulation in Children with Fragile X Syndrome

Region-specific microRNA alterations in marmosets carrying SLC6A4 polymorphisms are associated with anxiety-like behavior

Drugs used to treat bipolar disorder act via microRNAs to regulate expression of genes involved in neurite outgrowth

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