Glycogen Synthase Kinase-3β Haploinsufficiency Mimics the Behavioral and Molecular Effects of Lithium

O’Brien, William T.; Harper, Amber DeAra; Jové, Fernando; Woodgett, James R.; Maretto, Silvia; Piccolo, Stefano; Klein, Peter S.

doi:10.1523/jneurosci.4753-03.2004

Cited by 396 publications

(405 citation statements)

References 59 publications

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“…The neurotrophic effects of lithium in stressinduced hippocampal atrophy and antidepressant effects of this drug in rodent models (Wood et al, 2004;O'Brien et al, 2004) suggest a critical role of BDNF in these lithium-induced actions (reviewed in Chuang, 2004). Our results of lithium-induced suppression of PAI-1 transcription thus imply that PAI-1 may function as a target of lithium's neuroprotective and mood stabilizing effects through the PAI-1-tPA-plasmin pathway.…”

Section: Discussionmentioning

confidence: 70%

“…Besides direct inhibition, lithium has been shown to indirectly inhibit GSK-3 through phosphorylation of GSK-3α at Ser21 and GSK-3β at Ser9 by multiple mechanisms including the activation of PKA (Jope, 1999a), phosphatidylinositol 3-kinase (PI3-K)-dependent AKT (Chalecka-Franaszek and Chuang, 1999), protein kinase C (PKC) (Kirshenboim et al, 2004), as well as the involvement of GSK-3 autoregulation Liang and Chuang, 2007). GSK-3 inhibition is also likely involved in the anti-depressant and anti-manic effects of lithium observed in rodent models (Gould et al, 2004;Kaidanovich-Beilin et al, 2004;O'Brien et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling

Liang¹,

Wendland²,

Chuang³

2008

Molecular and Cellular Neuroscience

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Smad proteins are intracellular transducers for transforming growth factor-β (TGF-β signaling and play a critical role in differentiation, tissue repair and apoptosis of the central nervous system. Both TGF-β and its regulated gene, plasminogen activator inhibitor type-1 (PAI-1), have been implicated in the etiology and progression of neurodegenerative diseases and mood disorders. We previously reported that GSK-3β protein depletion suppresses Smad3/4-dependent gene transcription and causes a reduction in PAI-1 expression. Here, we provide evidence that lithium, the drug for the treatment and prophylaxis of bipolar disorder, inhibits Smad-dependent signaling by regulating cAMP-protein kinase A (PKA), AKT-glycogen synthase kinase-3β (GSK-3β), and CRE-dependent signaling pathways in neuron-enriched cerebral cortical cultures of rats. We demonstrate that lithium-induced activation of these pathways inhibits Smad3/4-dependent gene transcription through an increase in pCREB Ser133 protein levels, an enhanced interaction between pCREB Ser133 and p300/CBP, which causes Smad3/4-p300/CBP complex disruption and transcriptional suppression of Smad3/4-dependent genes. Therapeutic implications of our findings are discussed.

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Section: Discussionmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling

Liang¹,

Wendland²,

Chuang³

2008

Molecular and Cellular Neuroscience

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“…For example, lithium, GSK-3b knockout and other GSK-3 inhibitors show antidepressant effects in rodents. [39][40][41] Lithium and other GSK-3 inhibitors also attenuate the hyperactivity induced by amphetamine in rats 40 or dopamine transporter knockout in mice. 42 Valproic acid-induced promoter IV activation is mimicked by treatment with other HDAC inhibitors, SB and TSA, or by gene knockdown with HDAC1-specific siRNA (Figure 5), suggesting the involvement of HDAC inhibition.…”

Section: Discussionmentioning

confidence: 99%

The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons

et al. 2007

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Brain-derived neurotrophic factor (BDNF) has been strongly implicated in the synaptic plasticity, neuronal survival and pathophysiology of depression. Lithium and valproic acid (VPA) are two primary mood-stabilizing drugs used to treat bipolar disorder. Treatment of cultured rat cortical neurons with therapeutic concentrations of LiCl or VPA selectively increased the levels of exon IV (formerly rat exon III)-containing BDNF mRNA, and the activity of BDNF promoter IV. Surprisingly, lithium-or VPA-responsive element(s) in promoter IV resides in a region upstream from the calcium-responsive elements (CaREs) responsible for depolarization-induced BDNF induction. Moreover, activation of BDNF promoter IV by lithium or VPA occurred in cortical neurons depolarized with KCl, and deletion of these three CaREs did not abolish lithium-or VPA-induced activation. Lithium and VPA are direct inhibitors of glycogen synthase kinase-3 (GSK-3) and histone deacetylase (HDAC), respectively. We showed that lithium-induced activation of promoter IV was mimicked by pharmacological inhibition of GSK-3 or short interfering RNA (siRNA)-mediated gene silencing of GSK-3a or GSK-3b isoforms. Furthermore, treatment with other HDAC inhibitors, sodium butyrate and trichostatin A, or transfection with an HDAC1-specific siRNA also activated BDNF promoter IV. Our study demonstrates for the first time that GSK-3 and HDAC are respective initial targets for lithium and VPA to activate BDNF promoter IV, and that this BDNF induction involves a novel responsive region in promoter IV of the BDNF gene. Our results have strong implications for the therapeutic actions of these two mood stabilizers.

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“…Chronic lithium administration in rodents is reported to lead to reduced immobility in the forced-swim test (O'Brien et al, 2004), which suggests that the IMPA1 À/À mice might have a lithium-like phenotype in the forced-swim test, and thus, that this lithium effect is mediated by IMPA1 inhibition. We tried to evaluate this by studying the effect of chronic lithium administration on the observed reduced immobility in the IMPA1 À/À mice.…”

Section: Discussionmentioning

confidence: 99%

IMPA1 is Essential for Embryonic Development and Lithium-Like Pilocarpine Sensitivity

Cryns¹,

Shamir

Acker

et al. 2007

Neuropsychopharmacol

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Lithium has been the standard pharmacological treatment for bipolar disorder over the last 50 years; however, the molecular targets through which lithium exerts its therapeutic effects are still not defined. We characterized the phenotype of mice with a dysfunctional IMPA1 gene (IMPA1 À/À ) to study the in vivo physiological functions of IMPA1, in general, and more specifically its potential role as a molecular target in mediating lithium-dependent physiological effects. Homozygote IMPA1 À/À mice died in utero between days 9.5 and 10.5 post coitum (p.c.) demonstrating the importance of IMPA1 in early embryonic development. Intriguingly, the embryonic lethality could be reversed by myo-inositol supplementation via the pregnant mothers. In brains of adult IMPA1 À/À mice, IMPase activity levels were found to be reduced (up to 65% in hippocampus); however, inositol levels were not found to be altered. Behavioral analysis of the IMPA1 À/À mice indicated an increased motor activity in both the open-field test and the forced-swim test as well as a strongly increased sensitivity to pilocarpine-induced seizures, the latter supporting the idea that IMPA1 represents a physiologically relevant target for lithium. In conclusion the IMPA1 À/À mouse represents a novel model to study inositol homeostasis, and indicates that genetic inactivation of IMPA1 can mimic some actions of lithium.

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Glycogen Synthase Kinase-3β Haploinsufficiency Mimics the Behavioral and Molecular Effects of Lithium

Cited by 396 publications

References 59 publications

Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling

Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling

The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons

IMPA1 is Essential for Embryonic Development and Lithium-Like Pilocarpine Sensitivity

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