Wnt and GSK3 Signaling Pathways in Bipolar Disorder: Clinical and Therapeutic Implications

Muneer, Ather

doi:10.9758/cpn.2017.15.2.100

Cited by 84 publications

(53 citation statements)

References 51 publications

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“…Furthermore, escitalopram upregulates AKT activity by Ser473 phosphorylation [178]. The same effect as fluvoxamine [179], whereas paroxetine inhibits GSK3β via functional synergism with FK506 binding protein 51 [180]. Additionally, SSRIs regulate BDNF gene expression, which could explain a requirement of several weeks of treatment to achieve the full therapeutic effect.…”

Section: Selective Serotonin Reuptake Inhibitorsmentioning

confidence: 99%

GSK3β: A Master Player in Depressive Disorder Pathogenesis and Treatment Responsiveness

Duda

Hajka

Wójcicka

et al. 2020

Cells

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Glycogen synthase kinase 3β (GSK3β), originally described as a negative regulator of glycogen synthesis, is a molecular hub linking numerous signaling pathways in a cell. Specific GSK3β inhibitors have anti-depressant effects and reduce depressive-like behavior in animal models of depression. Therefore, GSK3β is suggested to be engaged in the pathogenesis of major depressive disorder, and to be a target and/or modifier of anti-depressants' action. In this review, we discuss abnormalities in the activity of GSK3β and its upstream regulators in different brain regions during depressive episodes. Additionally, putative role(s) of GSK3β in the pathogenesis of depression and the influence of anti-depressants on GSK3β activity are discussed.Cells 2020, 9, 727 2 of 26 any of the groups listed above. Additionally, electroconvulsive therapy, conducted for the first time in 1938, is still widely used in the treatment of MDD, especially in its drug-refractory form [5].Although the monoaminergic hypothesis has led to the invention of many successful therapeutic strategies based on the elevation of levels of NA and 5-HT in the synaptic cleft, it does not explain the anti-depressant effect of lithium and the rapid action of ketamine in the treatment of mood disorders [6]. Therefore, factors other than neurotransmission must be taken into consideration in the context of the MDD pathogenesis. One of them is glycogen synthase kinase 3β (GSK3β) signaling. Glycogen Synthase Kinase 3βGSK3 was isolated in 1980, from rabbit skeletal muscle, and described as a highly specific serine/threonine kinase for glycogen synthase [7]. There are two isozymes of GSK3, α and β, and both are expressed at similar levels in the mouse brain [8]. In the human brain, the β isozyme predominates [9]. Therefore, GSK3β is expected to be crucial for the human central nervous system functioning. The activity of GSK3β is regulated positively and negatively by phosphorylation on Tyr216 and Ser9, respectively [10,11]. Whereas phosphorylation of the residue Tyr216 occurs during the GSK3β translation process and results in a synthesis of the fully activated kinase, Ser9 phosphorylation seems to be the main regulatory modification during the enzyme lifespan [12]. Ser9-phosphorylated GSK3β remains inhibited, and dephosphorylation of the residue results in the disinhibition (activation) of the kinase.GSK3β is part of numerous cellular signaling pathways, and its activity can be regulated, directly or indirectly, by several kinases, phosphatases, and proteases. The wide spectrum of GSK3β substrates, including transcription factors, glycolytic enzymes, pro-and anti-apoptotic factors, mitochondrial channels, membrane receptors, and cytoskeleton-associated proteins, makes GSK3β a central point of the cell homeostasis maintenance [13]. The activity of GSK3β affects energy metabolism, cell survival, proliferation, apoptosis, membrane polarity, internalization of the synaptic receptors, neuroplasticity, neurotransmission, amyloid processing, and many other processes [13].Ex...

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Section: Selective Serotonin Reuptake Inhibitorsmentioning

confidence: 99%

GSK3β: A Master Player in Depressive Disorder Pathogenesis and Treatment Responsiveness

Duda

Hajka

Wójcicka

et al. 2020

Cells

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“…In particular, the activity of Wnt signaling is constitutively suppressed by the active form of GSK3b under basal condition (Muneer, 2017). The inactivation (phosphorylation) of GSK3b leads to dephosphorylation of b-catenin and activation of Wnt signaling to promote bone anabolism (Bertacchini et al, 2018).…”

Section: The Canonical Wingless (Wnt) Signaling Pathwaymentioning

confidence: 99%

The Skeletal-Protecting Action and Mechanisms of Action for Mood-Stabilizing Drug Lithium Chloride: Current Evidence and Future Potential Research Areas

Wong

Chin

2020

Front. Pharmacol.

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Lithium, the lightest natural-occurring alkali metal with an atomic number of three, stabilizes the mood to prevent episodes of acute manic and depression. Multiple lines of evidence point to lithium as an anti-suicidal, anti-viral, anti-cancer, immunomodulatory, neuroprotective and osteoprotective agent. This review article provides a comprehensive review of studies investigating the bone-enhancing effects of lithium and its possible underlying molecular mechanisms. Most of the animal experimental studies reported the beneficial effects of lithium in defective bones but not in healthy bones. In humans, the effects of lithium on bones remain heterogeneous. Mechanistically, lithium promotes osteoblastic activities by activating canonical Wingless (Wnt)/beta (b)-catenin, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) and bone morphogenetic protein-2 (BMP-2) transduction pathways but suppresses osteoclastic activities by inhibiting the receptor activator of nuclear factor-kappa B (RANK)/receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin (OPG) system, nuclear factorkappa B (NF-kB), mitogen-activated protein kinase (MAPK), and calcium signaling cascades. In conclusion, lithium confers protection to the skeleton but its clinical utility awaits further validation from human clinical trials.

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“…Schizophrenia (SCZ) and bipolar disorder (BD) are heterogeneous psychiatric disorders that manifest during late adolescence and young adulthood, and together affect~3.5% of the US adult population [1,2]. Pharmacological, genetic, postmortem, and animal studies have linked N-methyl-D-aspartate receptor (NMDA) hypofunction [3,4], impairments in dopamine [4][5][6], winglessrelated integration site (WNT) [7,8], or calcium signaling [9], and GABAergic gene expression deficits [10][11][12][13][14][15] to SCZ and/or BD. Moreover, an increasing number of studies have reported an upregulation in non-neuronal gene expression related to inflammation in the brain of subjects with SCZ [16][17][18][19][20][21][22] and less in BD [23], such as the acute-phase inflammation marker serpin family A member 3 (SERPINA3-also known as alpha 1-antichymotrypsin) [16,19,21].…”

Section: Introductionmentioning

confidence: 99%

Exosomal secretion of a psychosis-altered miRNA that regulates glutamate receptor expression is affected by antipsychotics

Amoah

Rodriguez

Logothetis

et al. 2019

Neuropsychopharmacol.

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The ability of small secretory microvesicles known as exosomes to influence neuronal and glial function via their microRNA (miRNA) cargo has positioned them as a novel and effective method of cell-to-cell communication. However, little is known about the role of exosome-secreted miRNAs in the regulation of glutamate receptor gene expression and their relevance for schizophrenia (SCZ) and bipolar disorder (BD). Using mature miRNA profiling and quantitative real-time PCR (qRT-PCR) in the orbitofrontal cortex (OFC) of SCZ (N = 29; 20 male and 9 female), BD (N = 26; 12 male and 14 female), and unaffected control (N = 25; 21 male and 4 female) subjects, we uncovered that miR-223, an exosome-secreted miRNA that targets glutamate receptors, was increased at the mature miRNA level in the OFC of SCZ and BD patients with positive history of psychosis at the time of death and was inversely associated with deficits in the expression of its targets glutamate ionotropic receptor NMDA-type subunit 2B (GRIN2B) and glutamate ionotropic receptor AMPA-type subunit 2 (GRIA2). Furthermore, changes in miR-223 levels in the OFC were positively and negatively correlated with inflammatory and GABAergic gene expression, respectively. Moreover, miR-223 was found to be enriched in astrocytes and secreted via exosomes, and antipsychotics were shown to control its cellular and exosomal localization in a cellspecific manner. Furthermore, addition of astrocytic exosomes in neuronal cultures resulted in a significant increase in miR-223 expression and a notable reduction in Grin2b and Gria2 mRNA levels, which was strongly inversely associated with miR-223 expression. Lastly, inhibition of astrocytic miR-223 abrogated the exosomal-mediated reduction in neuronal Grin2b expression. Taken together, our results demonstrate that the exosomal secretion of a psychosis-altered and glial-enriched miRNA that controls neuronal gene expression is regulated by antipsychotics.

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Wnt and GSK3 Signaling Pathways in Bipolar Disorder: Clinical and Therapeutic Implications

Cited by 84 publications

References 51 publications

GSK3β: A Master Player in Depressive Disorder Pathogenesis and Treatment Responsiveness

GSK3β: A Master Player in Depressive Disorder Pathogenesis and Treatment Responsiveness

The Skeletal-Protecting Action and Mechanisms of Action for Mood-Stabilizing Drug Lithium Chloride: Current Evidence and Future Potential Research Areas

Exosomal secretion of a psychosis-altered miRNA that regulates glutamate receptor expression is affected by antipsychotics

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