GSK3β Inhibition Promotes Synaptogenesis in Drosophila and Mammalian Neurons

Cuesto, Germán; Jordán-Álvarez, Sheila; Enriquez-Barreto, Lilian; Ferrús, Alberto; Morales, Miguel; Acebes, Ángel

doi:10.1371/journal.pone.0118475

Cited by 37 publications

(39 citation statements)

References 75 publications

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“…The important decrease in GSK3β expression levels and phosphorylation states between juvenile and adolescent/adult brains, presented here and in previous studies (Leroy et al ., ; Beurel et al ., ), may support this hypothesis. It has recently been demonstrated that GSK3β inhibition exhibits an age‐dependent effect on mammalian synaptogenesis (Cuesto et al ., ). GSK3β inhibition can repress/enhance synaptic formation depending on the age of the cultured neurons, suggesting that in young neurons, the mechanisms controlled by GSK3β differ from mature neurons.…”

Section: Discussionmentioning

confidence: 97%

Treatment with the GSK3‐beta inhibitor Tideglusib improves hippocampal development and memory performance in juvenile, but not adult, Cdkl5 knockout mice

Fuchs

Fustini

Trazzi

et al. 2018

Eur J of Neuroscience

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Cyclin-dependent kinase-like 5 (CDKL5) disorder is a severe neurodevelopmental disorder characterized by early-onset epileptic seizures, severe developmental delay, and intellectual disability. To date, no effective pharmacological treatments are available to improve the neurological phenotype that is due to mutations in the CDKL5 gene. Murine models of CDKL5 disorder have recently been generated, making the preclinical testing of pharmacological interventions possible. Using a Cdkl5 knockout (KO) mouse model, we recently demonstrated that deficiency of Cdkl5 causes defects in postnatal hippocampal development and hippocampus-dependent learning and memory. These defects were accompanied by an increased activity of GSK3β, an important inhibitory regulator of many neuronal functions. Pharmacological inhibition of GSK3β activity was able to recover hippocampal defects and cognitive performance in juvenile Cdkl5 KO mice, suggesting that GSK3β inhibitors might be a potential therapeutic option for CDKL5 disorder. As GSK3β inhibitors have been shown to have differential medication responses in young people and adults, this study was designed to examine whether GSK3β is a possible therapeutic target both in juvenile and in adult CDKL5 patients. We found that treatment with the GSK3β inhibitor Tideglusib during the juvenile period improved hippocampal development and hippocampus-dependent behaviors in Cdkl5 KO mice, while treatment later on in adulthood had no positive effects. These results suggest that pharmacological interventions aimed at normalizing impaired GSK3β activity might have different age-dependent outcomes in CDKL5 disorder. This is of utmost importance in the development of therapeutic approaches in CDKL5 patients and in the design of rational clinical trials.

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Section: Discussionmentioning

confidence: 97%

Treatment with the GSK3‐beta inhibitor Tideglusib improves hippocampal development and memory performance in juvenile, but not adult, Cdkl5 knockout mice

Fuchs

Fustini

Trazzi

et al. 2018

Eur J of Neuroscience

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“…This might be related to the BDNF-dependent GSK3β activity reduction. The Ser9 of GSK3β is highly phosphorylated upon stimulation of synaptogenesis, and the inhibition of the kinase is required for dendritic growth and arborization, whereas an increase in its activity leads to marked shrinkage of dendrites [94,95]. Moreover, in vivo overexpression of GSK3β reduces neurogenesis in adult hippocampus [96] and induces pro-depressant-like events [97].…”

Section: Bdnf-regulated Action Of Gsk3βmentioning

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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“…Aβ42 oligomers where added to the cell culture 72 h after cell seeding (48 h after differentiation), at 3 different concentrations (Kayed and Glabe, 2006). To stimulate PI3K activity we used the peptide PTD4-PI3KAc, previously proved to trigger PI3K activation both in vitro and in vivo (Cuesto et al, 2015(Cuesto et al, , 2011Enriquez-Barreto et al, 2014). PTD4-PI3KAc was administered at 3 different time points, before Aβ42 (pretreatment), simultaneously with Aβ42 (co-treatment) or after Aβ42 addition (posttreatment) (Fig.…”

Section: Pi3k Extends Cell Survival Of Human Neurons Exposed To Aβ42 mentioning

confidence: 99%

“…Furthermore, pharmacological administration of a PTEN membrane-permeable peptide, unable to interact with Aβ42, rescues synapse deterioration (Knafo et al, 2016). Other PI3K regulators, like the signaling inhibitor GSK3-β, are known to elicit anti-synaptogenic actions in Drosophila and mice (Cuesto et al, 2015;Martín-Peña et al, 2006), with concomitant effects in LTP and long-term memory (Hooper et al, 2008). In addition, Jun kinase/AP-1 and Wnt signaling are also members of the synaptogenic pathway, as they are regulated by GSK3-β (Franciscovich et al, 2008).…”

Section: Pi3k Mechanisms In Aβ42-induced Synapse Toxicitymentioning

confidence: 99%

“…The noncanonical PI3K-mediated pathway for synaptogenesis is counterbalanced by a Mad/Medea regulated anti-synaptogenesis pathway (Jordán-Álvarez et al, 2017). In turn, inhibitors of the PI3K pathway, as GSK3-β, reduce the number of synapses (Cuesto et al, 2015). Actually, genetic manipulations of GSK3-β attenuate or suppress several AD traits in Drosophila (Sofola et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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PI3K activation prevents Aβ42-induced synapse loss and favors insoluble amyloid deposits formation

Arnés

Romero

Casas‐Tintó

et al. 2019

Preprint

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Alzheimer's disease is, to a large extent, a disease of the synapse triggered by the unbalanced amyloidogenic cleavage of the amyloid precursor protein APP. Excess of Aβ42 peptide in particular is considered a hallmark of the disease. Here we drive the expression of the human Aβ42 peptide to assay the neuroprotective effects of PI3K in adult Drosophila melanogaster. We show that the neuronal expression of the human peptide elicits progressive toxicity in the adult. The pathological traits include reduced axonal transport, synapse loss, defective climbing ability and olfactory perception, as well as life-span reduction. The Aβ42-dependent synapse decay does not involve transcriptional changes in the core synaptic protein encoding genes: bruchpilot, liprin and synaptobrevin. All toxicity features, however, are suppressed by the co-expression of PI3K. Moreover, PI3K activation induces a significant increase of 6E10 and Thioflavin-positive amyloid deposits. Mechanistically, we suggest that Aβ42-Ser26 could be a candidate residue for direct or indirect phosphorylation by PI3K. Finally, along with these in vivo experiments we further analyze Aβ42 toxicity and its suppression by PI3K activation in in vitro assays with SH-SY5Y human neuroblastoma cell cultures, where Aβ42 aggregation into large insoluble deposits is reproduced. Taken together, these results uncover a potential novel pharmacological strategy against this disease with PI3K activation as a target.

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GSK3β Inhibition Promotes Synaptogenesis in Drosophila and Mammalian Neurons

Cited by 37 publications

References 75 publications

Treatment with the GSK3‐beta inhibitor Tideglusib improves hippocampal development and memory performance in juvenile, but not adult, Cdkl5 knockout mice

Treatment with the GSK3‐beta inhibitor Tideglusib improves hippocampal development and memory performance in juvenile, but not adult, Cdkl5 knockout mice

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

PI3K activation prevents Aβ42-induced synapse loss and favors insoluble amyloid deposits formation

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