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

Kidnapillai, Srisaiyini; Wade, Ben; Bortolasci, Chiara C.; Panizzutti, Bruna; Spolding, Briana; Connor, Timothy; Crowley, Tamsyn M.; Jamain, Stéphane; Gray, Laura J.; Leboyer, Marion; Berk, Michael; Walder, Ken

doi:10.1177/0269881119895534

Cited by 16 publications

(12 citation statements)

References 59 publications

(67 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Li has multiple direct and indirect targets, namely in Wnt, phosphatidylinositol and calcium signaling pathways, in mitochondrial functions and in neuronal excitability [ 25 – 30 ]. The cellular effects of Li are extensive since many of the downstream targets are transcription factors, miRNAs, histone modifications and DNA methylation, all of which multiply the molecular complexity of the treatment [ 31 , 32 ]. One of the most studied Li targets is glycogen synthase kinase 3 beta (GSK-3β), a component of the canonical or Wnt/β-catenin signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients

et al. 2021

View full text Add to dashboard Cite

Bipolar disorder (BD) is a psychiatric condition characterized by depressive and manic episodes that affect 2% of the world population. The first-line long-term treatment for mood stabilization is lithium (Li). Induced pluripotent stem cell modeling of BD using hippocampal dentate gyrus-like neurons derived from Li-responsive (LR) and Li-non-responsive (NR) patients previously showed neuronal hyperexcitability. Li treatment reversed hyperexcitability only on the LR neurons. In this study we searched for specific targets of Li resistance in NR neurons and found that the activity of Wnt/β-catenin signaling pathway was severely affected, with a significant decrease in expression of LEF1. Li targets the Wnt/βcatenin signaling pathway by inhibiting GSK-3β and releasing β-catenin that forms a nuclear complex with TCF/LEF1, activating the Wnt/β-catenin transcription program. Therefore, we propose that downregulation of LEF1 may account for Li resistance in NR neurons. Our results show that valproic acid (VPA), a drug used to treat NR patients that also acts downstream of GSK-3β, upregulated LEF1 and Wnt/β-catenin gene targets, increased transcriptional activity of complex β-catenin/TCF/LEF1 and reduced excitability in NR neurons. Additionally, decreasing LEF1 expression in control neurons using shLEF1 caused hyperexcitability, confirming that the impact of VPA on excitability in NR neurons was connected to changes in LEF1 and in the Wnt/β-catenin pathway. Our results suggest that LEF1 may be a useful target for the discovery of new drugs for BD treatment.

show abstract

Section: Introductionmentioning

confidence: 99%

Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients

et al. 2021

View full text Add to dashboard Cite

show abstract

“…For instance, a combination of drugs including lithium, valproate, lamotrigine and quetiapine has been shown to alter the expression of several genes including miRNAs in cultured human neurons. Among the differentially expressed genes have been miR-128 and miR-378 whose targets are enriched in neuron projection development and axonogenesis [ 53 ]. Thus, ncRNAs not only are involved in the pathogenesis of BD but also they might participate in the determination of response to prescribed drugs.…”

Section: Discussionmentioning

confidence: 99%

A Comprehensive Review on the Role of Non-Coding RNAs in the Pathophysiology of Bipolar Disorder

Ghafouri‐Fard

Badrlou

Taheri

et al. 2021

IJMS

View full text Add to dashboard Cite

Aim: Bipolar disorder is a multifactorial disorder being linked with dysregulation of several genes. Among the recently acknowledged factors in the pathophysiology of bipolar disorder are non-coding RNAs (ncRNAs). Methods: We searched PubMed and Google Scholar databases to find studies that assessed the expression profile of miRNAs, lncRNAs and circRNAs in bipolar disorder. Results: Dysregulated ncRNAs in bipolar patients have been enriched in several neuron-related pathways such as GABAergic and glutamatergic synapses, morphine addiction pathway and redox modulation. Conclusion: Altered expression of these transcripts in bipolar disorder provides clues for identification of the pathogenesis of this disorder and design of targeted therapies for the treatment of patients.

show abstract

“…In relation to novel mechanisms, it has been shown how miRNAs play an important role in neurogenesis and synaptogenesis [ 116 , 117 ], and that the expression of several miRNAs are changed in humans and rats by common mood stabilizers, including lithium [ 118 , 119 ]. For example, Chen et al [ 119 ] showed that lithium increased the expression of four miRNAs (miR-34a, miR-152, miR-155 and miR-221) in lymphoblastoid cell lines derived from BD patients, while another study found that mood stabilizers tend to increase the expression of miR-128 and miR-378, which are involved in neuron maturation and synaptogenesis [ 120 ].…”

Section: Pharmacological Treatments and Ahn In Animal Models And Humansmentioning

confidence: 99%

Is Adult Hippocampal Neurogenesis Really Relevant for the Treatment of Psychiatric Disorders?

Carli

Aringhieri

Kolachalam

et al. 2021

View full text Add to dashboard Cite

: Adult neurogenesis consists in the generation of newborn neurons from neural stem cells taking place in the adult brain. In mammals, this process is limited to very few areas of the brain, and one of these neurogenic niches is the subgranular layer of the dentate gyrus (DG) of the hippocampus. Adult newborn neurons are generated from quiescent neural progenitors (QNPs), which differentiate through different steps into mature granule cells (GCs), to be finally integrated into the existing hippocampal circuitry. In animal models, adult hippocampal neurogenesis (AHN) is relevant for pattern discrimination, cognitive flexibility, emotional processing and resilience to stressful situations. Imaging techniques allow to visualize newborn neurons within the hippocampus through all their stages of development and differentiation. In humans, the evidence of AHN is more challenging, and, based on recent findings, it persists through the adulthood, even if it declines with age. Whether this process has an important role in human brain function and how it integrates into the existing hippocampal circuitry is still a matter of exciting debate. Importantly, AHN deficiency has been proposed to be relevant in many psychiatric disorders, including mood disorders, anxiety, post-traumatic stress disorder and schizophrenia. This review aims to investigate how AHN is altered in different psychiatric conditions and how pharmacological treatments can rescue this process. In fact, many psychoactive drugs, such as antidepressants, mood stabilizers and atypical antipsychotics (AAPs), can boost AHN with different results. In addition, some non-pharmacological approaches are discussed as well.

show abstract

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

Cited by 16 publications

References 59 publications

Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients

Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients

A Comprehensive Review on the Role of Non-Coding RNAs in the Pathophysiology of Bipolar Disorder

Is Adult Hippocampal Neurogenesis Really Relevant for the Treatment of Psychiatric Disorders?

Contact Info

Product

Resources

About