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The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons.
Mol Psychiatry. 2009 Jan; 14(1):51-9.MP

Abstract

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-3alpha or GSK-3beta 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.

Authors+Show Affiliations

Yasuda S
Molecular Neurobiology Section, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1363, USA.
Liang MH
No affiliation info available
Marinova Z
No affiliation info available
Yahyavi A
No affiliation info available
Chuang DM
No affiliation info available

MeSH

AnimalsAntimanic AgentsBrain-Derived Neurotrophic FactorCells, CulturedCerebral CortexDose-Response Relationship, DrugEmbryo, MammalianEnzyme InhibitorsEnzyme-Linked Immunosorbent AssayLithium ChlorideMembrane PotentialsNeuronsPatch-Clamp TechniquesPotassium ChloridePromoter Regions, GeneticRNA, MessengerRNA, Small InterferingRatsTime FactorsTransfectionValproic Acid

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural

Language

eng

PubMed ID

17925795

Clinical Trial Links

Dual Treatment With Lithium and Valproate in ALS.

Citation

Yasuda, S, et al. "The Mood Stabilizers Lithium and Valproate Selectively Activate the Promoter IV of Brain-derived Neurotrophic Factor in Neurons." Molecular Psychiatry, vol. 14, no. 1, 2009, pp. 51-9.
Yasuda S, Liang MH, Marinova Z, et al. The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons. Mol Psychiatry. 2009;14(1):51-9.
Yasuda, S., Liang, M. H., Marinova, Z., Yahyavi, A., & Chuang, D. M. (2009). The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons. Molecular Psychiatry, 14(1), 51-9.
Yasuda S, et al. The Mood Stabilizers Lithium and Valproate Selectively Activate the Promoter IV of Brain-derived Neurotrophic Factor in Neurons. Mol Psychiatry. 2009;14(1):51-9. PubMed PMID: 17925795.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons. AU - Yasuda,S, AU - Liang,M-H, AU - Marinova,Z, AU - Yahyavi,A, AU - Chuang,D-M, Y1 - 2007/10/09/ PY - 2007/10/11/pubmed PY - 2009/4/9/medline PY - 2007/10/11/entrez SP - 51 EP - 9 JF - Molecular psychiatry JO - Mol Psychiatry VL - 14 IS - 1 N2 - 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-3alpha or GSK-3beta 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. SN - 1476-5578 UR - https://www.unboundmedicine.com/medline/citation/17925795/The_mood_stabilizers_lithium_and_valproate_selectively_activate_the_promoter_IV_of_brain_derived_neurotrophic_factor_in_neurons_ DB - PRIME DP - Unbound Medicine ER -