Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Valproate reverses mania-like behaviors in mice via preferential targeting of HDAC2

Molecular Psychiatry volume 26, pages 4066–4084 (2021)Cite this article

Subjects

Abstract

Valproate (VPA) has been used in the treatment of bipolar disorder since the 1990s. However, the therapeutic targets of VPA have remained elusive. Here we employ a preclinical model to identify the therapeutic targets of VPA. We find compounds that inhibit histone deacetylase proteins (HDACs) are effective in normalizing manic-like behavior, and that class I HDACs (e.g., HDAC1 and HDAC2) are most important in this response. Using an RNAi approach, we find that HDAC2, but not HDAC1, inhibition in the ventral tegmental area (VTA) is sufficient to normalize behavior. Furthermore, HDAC2 overexpression in the VTA prevents the actions of VPA. We used RNA sequencing in both mice and human induced pluripotent stem cells (iPSCs) derived from bipolar patients to further identify important molecular targets. Together, these studies identify HDAC2 and downstream targets for the development of novel therapeutics for bipolar mania.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: VPA and HDAC inhibition via SAHA reverse manic-like behaviors in ClockΔ19 mice.
Fig. 2: Class I HDAC inhibition via MS275 normalizes manic-like behavior in ClockΔ19 mice.
Fig. 3: Inhibition of HDAC1 and 2 via ACY957 normalizes manic-like behavior in ClockΔ19 mice.
Fig. 4: Knockdown of HDAC2, but not HDAC1, in the VTA normalizes manic-like behavior in ClockΔ19 mice.
Fig. 5: The effects of VPA and ACY957 on the VTA transcriptome of ClockΔ19 mutant mice and patient-derived human iPSCs.

Similar content being viewed by others

References

  1. Lopez-Munoz F, Shen WW, D’Ocon P, Romero A, Alamo C. A history of the pharmacological treatment of bipolar disorder. Int J Mol Sci. 2018;19:2143.

    PubMed Central  Google Scholar 

  2. Macdonald RL, Kelly KM. Antiepileptic drug mechanisms of action. Epilepsia. 1995;36:S2–12.

    CAS  PubMed  Google Scholar 

  3. Gould TD, Quiroz JA, Singh J, Zarate CA, Manji HK. Emerging experimental therapeutics for bipolar disorder: insights from the molecular and cellular actions of current mood stabilizers. Mol Psychiatry. 2004;9:734–55.

    CAS  PubMed  Google Scholar 

  4. Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem. 2001;276:36734–41.

    CAS  PubMed  Google Scholar 

  5. Chiu CT, Wang Z, Hunsberger JG, Chuang DM. Therapeutic potential of mood stabilizers lithium and valproic acid: beyond bipolar disorder. Pharmacol Rev. 2013;65:105–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Nestler EJ, Pena CJ, Kundakovic M, Mitchell A, Akbarian S. Epigenetic basis of mental illness. Neuroscientist. 2016;22:447–63.

    CAS  PubMed  Google Scholar 

  7. Morris MJ, Monteggia LM. Unique functional roles for class I and class II histone deacetylases in central nervous system development and function. Int J Dev Neurosci. 2013;31:370–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Dai Y, Faller DV. Transcription regulation by class III histone deacetylases (HDACs)-sirtuins. Transl Oncogenomics. 2008;3:53–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Baltan S, Bachleda A, Morrison RS, Murphy SP. Expression of histone deacetylases in cellular compartments of the mouse brain and the effects of ischemia. Transl Stroke Res. 2011;2:411–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Ryu H, Lee J, Olofsson BA, Mwidau A, Dedeoglu A, Escudero M, et al. Histone deacetylase inhibitors prevent oxidative neuronal death independent of expanded polyglutamine repeats via an Sp1-dependent pathway. Proc Natl Acad Sci USA. 2003;100:4281–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Machado-Vieira R, Ibrahim L, Zarate CA Jr. Histone deacetylases and mood disorders: epigenetic programming in gene-environment interactions. CNS Neurosci Ther. 2011;17:699–704.

    CAS  PubMed  Google Scholar 

  12. Benes FM, Lim B, Matzilevich D, Walsh JP, Subburaju S, Minns M. Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars. Proc Natl Acad Sci USA. 2007;104:10164–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Tseng CJ, Gilbert TM, Catanese MC, Hightower BG, Peters AT, Parmar AJ, et al. In vivo human brain expression of histone deacetylases in bipolar disorder. Transl Psychiatry. 2020;10:224.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Arent CO, Valvassori SS, Fries GR, Stertz L, Ferreira CL, Lopes-Borges J, et al. Neuroanatomical profile of antimaniac effects of histone deacetylases inhibitors. Mol Neurobiol. 2011;43:207–14.

    CAS  PubMed  Google Scholar 

  15. Varela RB, Resende WR, Dal-Pont GC, Gava FF, Tye SJ, Quevedo J, et al. HDAC inhibitors reverse mania-like behavior and modulate epigenetic regulatory enzymes in an animal model of mania induced by Ouabain. Pharmacol Biochem Behav. 2020;193:172917.

    CAS  PubMed  Google Scholar 

  16. McClung CA, Sidiropoulou K, Vitaterna M, Takahashi JS, White FJ, Cooper DC, et al. Regulation of dopaminergic transmission and cocaine reward by the Clock gene. Proc Natl Acad Sci USA. 2005;102:9377–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Roybal K, Theobold D, Graham A, DiNieri JA, Russo SJ, Krishnan V, et al. Mania-like behavior induced by disruption of CLOCK. Proc Natl Acad Sci USA. 2007;104:6406–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Arey R, McClung CA. An inhibitor of casein kinase 1 epsilon/delta partially normalizes the manic-like behaviors of the ClockDelta19 mouse. Behav= Pharmacol. 2012;23:392–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Arey RN, Enwright JF 3rd, Spencer SM, Falcon E, Ozburn AR, Ghose S, et al. An important role for cholecystokinin, a CLOCK target gene, in the development and treatment of manic-like behaviors. Mol Psychiatry. 2014;19:342–50.

    CAS  PubMed  Google Scholar 

  20. Sidor MM, Spencer SM, Dzirasa K, Parekh PK, Tye KM, Warden MR, et al. Daytime spikes in dopaminergic activity drive rapid mood-cycling in mice. Mol Psychiatry. 2015;20:1406–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Logan RW, McClung CA. Animal models of bipolar mania: the past, present and future. Neuroscience. 2016;321:163–88.

    CAS  PubMed  Google Scholar 

  22. Parekh PK, Sidor MM, Gillman A, Becker-Krail D, Bettelini L, Arban R, et al. Antimanic efficacy of a novel Kv3 potassium channel modulator. Neuropsychopharmacology. 2018;43:435–44.

    CAS  PubMed  Google Scholar 

  23. King DP, Takahashi JS. Molecular genetics of circadian rhythms in mammals. Annu Rev Neurosci. 2000;23:713–42.

    CAS  PubMed  Google Scholar 

  24. King DP, Zhao Y, Sangoram AM, Wilsbacher LD, Tanaka M, Antoch MP, et al. Positional cloning of the mouse circadian clock gene. Cell. 1997;89:641–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Naylor E, Bergmann BM, Krauski K, Zee PC, Takahashi JS, Vitaterna MH, et al. The circadian clock mutation alters sleep homeostasis in the mouse. J Neurosci. 2000;20:8138–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Easton A, Arbuzova J, Turek FW. The circadian Clock mutation increases exploratory activity and escape-seeking behavior. Genes Brain Behav. 2003;2:11–19.

    CAS  PubMed  Google Scholar 

  27. Ozburn AR, Falcon E, Mukherjee S, Gillman A, Arey R, Spencer S, et al. The role of clock in ethanol-related behaviors. Neuropsychopharmacology. 2013;38:2393–2400.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Ozburn AR, Larson EB, Self DW, McClung CA. Cocaine self-administration behaviors in ClockDelta19 mice. Psychopharmacology. 2012;223:169–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. van Enkhuizen J, Minassian A, Young JW. Further evidence for ClockDelta19 mice as a model for bipolar disorder mania using cross-species tests of exploration and sensorimotor gating. Behav Brain Res. 2013;249:44–54.

    PubMed  PubMed Central  Google Scholar 

  30. McClung CA, Nestler EJ, Zachariou V. Regulation of gene expression by chronic morphine and morphine withdrawal in the locus ceruleus and ventral tegmental area. J Neurosci. 2005;25:6005–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Coque L, Mukherjee S, Cao JL, Spencer S, Marvin M, Falcon E, et al. Specific role of VTA dopamine neuronal firing rates and morphology in the reversal of anxiety-related, but not depression-related behavior in the ClockDelta19 mouse model of mania. Neuropsychopharmacology. 2011;36:1478–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Mukherjee S, Coque L, Cao JL, Kumar J, Chakravarty S, Asaithamby A, et al. Knockdown of Clock in the ventral tegmental area through RNA interference results in a mixed state of mania and depression-like behavior. Biol Psychiatry. 2010;68:503–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Berk M, Dodd S, Kauer-Sant’anna M, Malhi GS, Bourin M, Kapczinski F, et al. Dopamine dysregulation syndrome: implications for a dopamine hypothesis of bipolar disorder. Acta Psychiatr Scand Supplementu. 2007;434:41–9.

    Google Scholar 

  34. Ashok AH, Marques TR, Jauhar S, Nour MM, Goodwin GM, Young AH, et al. The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment. Mol Psychiatry. 2017;22:666–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Abler B, Greenhouse I, Ongur D, Walter H, Heckers S. Abnormal reward system activation in mania. Neuropsychopharmacology. 2008;33:2217–27.

    CAS  PubMed  Google Scholar 

  36. van Enkhuizen J, Geyer MA, Kooistra K, Young JW. Chronic valproate attenuates some, but not all, facets of mania-like behaviour in mice. Int J Neuropsychopharmacol. 2013;16:1021–31.

    PubMed  Google Scholar 

  37. Simonini MV, Camargo LM, Dong E, Maloku E, Veldic M, Costa E, et al. The benzamide MS-275 is a potent, long-lasting brain region-selective inhibitor of histone deacetylases. Proc Natl Acad Sci USA. 2006;103:1587–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Kassis H, Shehadah A, Li C, Zhang Y, Cui Y, Roberts C, et al. Class IIa histone deacetylases affect neuronal remodeling and functional outcome after stroke. Neurochem Int. 2016;96:24–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Logan RW, Parekh PK, Kaplan GN, Becker-Krail DD, Williams WP 3rd, Yamaguchi S, et al. NAD+ cellular redox and SIRT1 regulate the diurnal rhythms of tyrosine hydroxylase and conditioned cocaine reward. Mol Psychiatry 2018;24:1668–84.

    PubMed  PubMed Central  Google Scholar 

  40. Ang SL. Transcriptional control of midbrain dopaminergic neuron development. Development. 2006;133:3499–506.

    CAS  PubMed  Google Scholar 

  41. Lydall GJ, Bass NJ, McQuillin A, Lawrence J, Anjorin A, Kandaswamy R, et al. Confirmation of prior evidence of genetic susceptibility to alcoholism in a genome-wide association study of comorbid alcoholism and bipolar disorder. Psychiatr Genet. 2011;21:294–306.

    PubMed  PubMed Central  Google Scholar 

  42. McCarthy MJ, Nievergelt CM, Kelsoe JR, Welsh DK. A survey of genomic studies supports association of circadian clock genes with bipolar disorder spectrum illnesses and lithium response. PLoS ONE. 2012;7:e32091.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Langfelder P, Luo R, Oldham MC, Horvath S. Is my network module preserved and reproducible? PLoS Comput Biol. 2011;7:e1001057.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Stern S, Santos R, Marchetto MC, Mendes APD, Rouleau GA, Biesmans S, et al. Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients’ responsiveness to lithium. Mol Psychiatry. 2018;23:1453–65.

    CAS  PubMed  Google Scholar 

  45. Mertens J, Wang QW, Kim Y, Yu DX, Pham S, Yang B, et al. Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature. 2015;527:95–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Tobe BTD, Crain AM, Winquist AM, Calabrese B, Makihara H, Zhao WN, et al. Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis. Proc Natl Acad Sci USA. 2017;114:E4462–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10:1523.

    PubMed  PubMed Central  Google Scholar 

  48. Delcuve GP, Khan DH, Davie JR. Roles of histone deacetylases in epigenetic regulation: emerging paradigms from studies with inhibitors. Clin Epigenetics. 2012;4:5.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Marks PA, Dokmanovic M. Histone deacetylase inhibitors: discovery and development as anticancer agents. Expert Opin Investig Drugs. 2005;14:1497–511.

    CAS  PubMed  Google Scholar 

  50. Bubna AK. Vorinostat—an overview. Indian J Dermatol. 2015;60:419.

    PubMed  PubMed Central  Google Scholar 

  51. Shearstone JR, Golonzhka O, Chonkar A, Tamang D, van Duzer JH, Jones SS, et al. Chemical inhibition of histone deacetylases 1 and 2 induces fetal hemoglobin through activation of GATA2. PloS ONE. 2016;11:e0153767.

    PubMed  PubMed Central  Google Scholar 

  52. Lima IVA, Almeida-Santos AF, Ferreira-Vieira TH, Aguiar DC, Ribeiro FM, Campos AC, et al. Antidepressant-like effect of valproic acid-Possible involvement of PI3K/Akt/mTOR pathway. Behav Brain Res. 2017;329:166–71.

    CAS  PubMed  Google Scholar 

  53. Schroeder FA, Lewis MC, Fass DM, Wagner FF, Zhang YL, Hennig KM, et al. A selective HDAC 1/2 inhibitor modulates chromatin and gene expression in brain and alters mouse behavior in two mood-related tests. PLoS ONE. 2013;8:e71323.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Can A, Blackwell RA, Piantadosi SC, Dao DT, O’Donnell KC, Gould TD. Antidepressant-like responses to lithium in genetically diverse mouse strains. Genes Brain Behav. 2011;10:434–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. White K, Bohart R, Whipple K, Boyd J. Lithium effects on normal subjects. Relationships to plasma and RBC lithium levels. Int Pharmacopsychiatry. 1979;14:176–83.

    CAS  PubMed  Google Scholar 

  56. Aldenkamp AP, Arends J, Bootsma HP, Diepman L, Hulsman J, Lambrechts D, et al. Randomized double-blind parallel-group study comparing cognitive effects of a low-dose lamotrigine with valproate and placebo in healthy volunteers. Epilepsia. 2002;43:19–26.

    CAS  PubMed  Google Scholar 

  57. Cipriani A, Reid K, Young AH, Macritchie K, Geddes J. Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder. Cochrane Database Syst Rev. 2013:CD003196.

  58. Hallahan B, Newell J, Soares JC, Brambilla P, Strakowski SM, Fleck DE, et al. Structural magnetic resonance imaging in bipolar disorder: an international collaborative mega-analysis of individual adult patient data. Biol Psychiatry. 2011;69:326–35.

    PubMed  Google Scholar 

  59. Hibar DP, Westlye LT, Doan NT, Jahanshad N, Cheung JW, Ching CRK, et al. Cortical abnormalities in bipolar disorder: an MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group. Mol Psychiatry. 2018;23:932–42.

    CAS  PubMed  Google Scholar 

  60. Strakowski SM, Eliassen JC, Lamy M, Cerullo MA, Allendorfer JB, Madore M, et al. Functional magnetic resonance imaging brain activation in bipolar mania: evidence for disruption of the ventrolateral prefrontal-amygdala emotional pathway. Biol Psychiatry. 2011;69:381–8.

    PubMed  Google Scholar 

  61. Milienne-Petiot M, Kesby JP, Graves M, van Enkhuizen J, Semenova S, Minassian A, et al. The effects of reduced dopamine transporter function and chronic lithium on motivation, probabilistic learning, and neurochemistry in mice: modeling bipolar mania. Neuropharmacology. 2017;113:260–70.

    CAS  PubMed  Google Scholar 

  62. Young JW, Cope ZA, Romoli B, Schrurs E, Aniek J, van Enkhuizen J, et al. Mice with reduced DAT levels recreate seasonal-induced switching between states in bipolar disorder. Neuropsychopharmacology. 2018;43:1721–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Meylan EM, Halfon O, Magistretti PJ, Cardinaux JR. The HDAC inhibitor SAHA improves depressive-like behavior of CRTC1-deficient mice: possible relevance for treatment-resistant depression. Neuropharmacology. 2016;107:111–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Covington HE 3rd, Maze I, Vialou V, Nestler EJ. Antidepressant action of HDAC inhibition in the prefrontal cortex. Neuroscience. 2015;298:329–35.

    CAS  PubMed  Google Scholar 

  65. Eom GH, Nam YS, Oh JG, Choe N, Min HK, Yoo EK, et al. Regulation of acetylation of histone deacetylase 2 by p300/CBP-associated factor/histone deacetylase 5 in the development of cardiac hypertrophy. Circ Res. 2014;114:1133–43.

    CAS  PubMed  Google Scholar 

  66. Choubey SK, Jeyakanthan J. Molecular dynamics and quantum chemistry-based approaches to identify isoform selective HDAC2 inhibitor—a novel target to prevent Alzheimer’s disease. J Recept Signal Transduct Res. 2018;38:266–78.

    CAS  PubMed  Google Scholar 

  67. Tan Y, Delvaux E, Nolz J, Coleman PD, Chen S, Mastroeni D. Upregulation of histone deacetylase 2 in laser capture nigral microglia in Parkinson’s disease. Neurobiol Aging. 2018;68:134–41.

    CAS  PubMed  Google Scholar 

  68. Laugesen A, Helin K. Chromatin repressive complexes in stem cells, development, and cancer. Cell Stem Cell. 2014;14:735–51.

    CAS  PubMed  Google Scholar 

  69. Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J, et al. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature. 2009;459:55–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Gonzalez-Zuniga M, Contreras PS, Estrada LD, Chamorro D, Villagra A, Zanlungo S, et al. c-Abl stabilizes HDAC2 levels by tyrosine phosphorylation repressing neuronal gene expression in Alzheimer’s disease. Mol Cell. 2014;56:163–73.

    CAS  PubMed  Google Scholar 

  71. Maletic V, Raison C. Integrated neurobiology of bipolar disorder. Front Psychiatry. 2014;5:98.

    PubMed  PubMed Central  Google Scholar 

  72. de la Fuente Revenga M, Ibi D, Saunders JM, Cuddy T, Ijaz MK, Toneatti R, et al. HDAC2-dependent antipsychotic-like effects of chronic treatment with the HDAC inhibitor SAHA in mice. Neuroscience. 2018;388:102–17.

    PubMed  Google Scholar 

  73. Limanaqi F, Biagioni F, Busceti CL, Ryskalin L, Fornai F. The effects of proteasome on baseline and methamphetamine-dependent dopamine transmission. Neurosci Biobehav Rev. 2019;102:308–17.

    CAS  PubMed  Google Scholar 

  74. Lauridsen JB, Johansen JL, Rekling JC, Thirstrup K, Moerk A, Sager TN. Regulation of the Bcas1 and Baiap3 transcripts in the subthalamic nucleus in mice recovering from MPTP toxicity. Neurosci Res. 2011;70:269–76.

    CAS  PubMed  Google Scholar 

  75. Ishimoto T, Ninomiya K, Inoue R, Koike M, Uchiyama Y, Mori H. Mice lacking BCAS1, a novel myelin-associated protein, display hypomyelination, schizophrenia-like abnormal behaviors, and upregulation of inflammatory genes in the brain. Glia. 2017;65:727–39.

    PubMed  Google Scholar 

  76. You C, Savarese A, Vandegrift BJ, He D, Pandey SC, Lasek AW, et al. Ethanol acts on KCNK13 potassium channels in the ventral tegmental area to increase firing rate and modulate binge-like drinking. Neuropharmacology. 2019;144:29–36.

    CAS  PubMed  Google Scholar 

  77. Judy JT, Zandi PP. A review of potassium channels in bipolar disorder. Front Genet. 2013;4:105.

    PubMed  PubMed Central  Google Scholar 

  78. Avram S, Shaposhnikov S, Buiu C, Mernea M. Chondroitin sulfate proteoglycans: structure-function relationship with implication in neural development and brain disorders. Biomed Res Int. 2014;2014:642798.

    PubMed  PubMed Central  Google Scholar 

  79. Ganai SA, Ramadoss M, Mahadevan V. Histone deacetylase (HDAC) inhibitors—emerging roles in neuronal memory, learning, synaptic plasticity and neural regeneration. Curr Neuropharmacol. 2016;14:55–71.

    CAS  PubMed  Google Scholar 

  80. Yamakawa H, Cheng J, Penney J, Gao F, Rueda R, Wang J, et al. The transcription factor Sp3 cooperates with HDAC2 to regulate synaptic function and plasticity in neurons. Cell Rep. 2017;20:1319–34.

    CAS  PubMed  Google Scholar 

  81. Kramer OH, Zhu P, Ostendorff HP, Golebiewski M, Tiefenbach J, Peters MA, et al. The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2. EMBO J. 2003;22:3411–20.

    PubMed  PubMed Central  Google Scholar 

  82. Spengler ML, Kuropatwinski KK, Comas M, Gasparian AV, Fedtsova N, Gleiberman AS, et al. Core circadian protein CLOCK is a positive regulator of NF-kappaB-mediated transcription. Proc Natl Acad Sci USA. 2012;109:E2457–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Wagner T, Kiweler N, Wolff K, Knauer SK, Brandl A, Hemmerich P, et al. Sumoylation of HDAC2 promotes NF-kappaB-dependent gene expression. Oncotarget. 2015;6:7123–35.

    PubMed  PubMed Central  Google Scholar 

  84. Ashburner BP, Westerheide SD, Baldwin AS Jr. The p65 (RelA) subunit of NF-kappaB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression. Mol Cell Biol. 2001;21:7065–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Howard AD, Wang R, Pong SS, Mellin TN, Strack A, Guan XM, et al. Identification of receptors for neuromedin U and its role in feeding. Nature. 2000;406:70–4.

    CAS  PubMed  Google Scholar 

  86. Vallof D, Vestlund J, Engel JA, Jerlhag E. The anorexigenic peptide neuromedin U (NMU) attenuates amphetamine-induced locomotor stimulation, accumbal dopamine release and expression of conditioned place preference in mice. PloS ONE. 2016;11:e0154477.

    PubMed  PubMed Central  Google Scholar 

  87. Graham ES, Littlewood P, Turnbull Y, Mercer JG, Morgan PJ, Barrett P. Neuromedin-U is regulated by the circadian clock in the SCN of the mouse. Eur J Neurosci. 2005;21:814–9.

    PubMed  Google Scholar 

  88. Lee IT, Chang AS, Manandhar M, Shan Y, Fan J, Izumo M, et al. Neuromedin s-producing neurons act as essential pacemakers in the suprachiasmatic nucleus to couple clock neurons and dictate circadian rhythms. Neuron. 2015;85:1086–102.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Harvey AG. Sleep and circadian rhythms in bipolar disorder: seeking synchrony, harmony, and regulation. Am J Psychiatry. 2008;165:820–9.

    PubMed  Google Scholar 

  90. Landgraf D, Joiner WJ, McCarthy MJ, Kiessling S, Barandas R, Young JW, et al. The mood stabilizer valproic acid opposes the effects of dopamine on circadian rhythms. Neuropharmacology. 2016;107:262–70.

    CAS  PubMed  Google Scholar 

  91. Gekakis N, Staknis D, Nguyen HB, Davis FC, Wilsbacher LD, King DP, et al. Role of the CLOCK protein in the mammalian circadian mechanism. Science. 1998;280:1564–9.

    CAS  PubMed  Google Scholar 

  92. Hao Y, Creson T, Zhang L, Li P, Du F, Yuan P, et al. Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis. J Neurosci. 2004;24:6590–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Cui SS, Yang CP, Bowen RC, Bai O, Li XM, Jiang W, et al. Valproic acid enhances axonal regeneration and recovery of motor function after sciatic nerve axotomy in adult rats. Brain Res. 2003;975:229–36.

    CAS  PubMed  Google Scholar 

  94. Hockly E, Richon VM, Woodman B, Smith DL, Zhou X, Rosa E, et al. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington’s disease. Proc Natl Acad Sci USA. 2003;100:2041–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Kurita M, Holloway T, Garcia-Bea A, Kozlenkov A, Friedman AK, Moreno JL, et al. HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity. Nat Neurosci. 2012;15:1245–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci. 2006;9:519–25.

    CAS  PubMed  Google Scholar 

  97. Singec I, Crain AM, Hou J, Tobe BTD, Talantova M, Winquist AA, et al. Quantitative analysis of human pluripotency and neural specification by in-depth (Phospho)proteomic profiling. Stem Cell Rep. 2016;7:527–42.

    CAS  Google Scholar 

  98. Li W, Sun W, Zhang Y, Wei W, Ambasudhan R, Xia P, et al. Rapid induction and long-term self-renewal of primitive neural precursors from human embryonic stem cells by small molecule inhibitors. Proc Natl Acad Sci USA. 2011;108:8299–304.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Madison JM, Zhou F, Nigam A, Hussain A, Barker DD, Nehme R, et al. Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities. Mol Psychiatry. 2015;20:703–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Maroof AM, Keros S, Tyson JA, Ying SW, Ganat YM, Merkle FT. et al. Directed differentiation and functional maturation of cortical interneurons from human embryonic stem cells. Cell Stem Cell. 2013;12:559–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Hunsberger JG, Austin DR, Chen G, Manji HK. Cellular mechanisms underlying affective resiliency: the role of glucocorticoid receptor- and mitochondrially-mediated plasticity. Brain Res. 2009;1293:76–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg SL. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 2013;14:R36.

    PubMed  PubMed Central  Google Scholar 

  103. Anders S, Pyl PT, Huber W. HTSeq–a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31:166–9.

    CAS  PubMed  Google Scholar 

  104. Volk DW, Matsubara T, Li S, Sengupta EJ, Georgiev D, Minabe Y, et al. Deficits in transcriptional regulators of cortical parvalbumin neurons in schizophrenia. Am J Psychiatry. 2012;169:1082–91.

    PubMed  PubMed Central  Google Scholar 

  105. Pertea M, Kim D, Pertea GM, Leek JT, Salzberg SL. Transcript-level expression analysis of RNA-seq experiments with HISAT, StringTie and Ballgown. Nat Protoc. 2016;11:1650–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Fischer A, Sananbenesi F, Wang X, Dobbin M, Tsai LH. Recovery of learning and memory is associated with chromatin remodelling. Nature. 2007;447:178–82.

    CAS  PubMed  Google Scholar 

  107. Zhang B, Horvath S. A general framework for weighted gene co-expression network analysis. Stat Appl Gen Mol Biol. 2005;4:Article17.

  108. Langfelder P, Zhang B, Horvath S. Defining clusters from a hierarchical cluster tree: the Dynamic Tree Cut package for R. Bioinformatics. 2008;24:719–20.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Heather Buresch, Mark Brown, and Emily W. Sedlock for mouse husbandry, coordination, and genotyping. The studies were supported by an IMHRO Rising Star Award, the Brain and Behavior Research Foundation (NARSAD Independent Investigator Award), MH106460, MH115241, MH111601 to CAM; Brain and Behavior Research Foundation (NARSAD Young Investigator Award), K01DA038654 to RWL.

Author information

Authors and Affiliations

  1. Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA

    Ryan W. Logan, Kyle D. Ketchesin, Darius Becker-Krail, Xiyu Zhu, Ethan Fitzgerald, Hui Zhang, Jeffrey Oliver-Smith, Lauren M. DePoy, Mariah A. Hildebrand & Colleen A. McClung

  2. Department of Behavioral Neuroscience, Portland Alcohol Research Center, Oregon Health & Science University, Portland, OR, 97239, USA

    Angela R. Ozburn

  3. VA Portland Health Care System, Portland, OR, 97239, USA

    Angela R. Ozburn

  4. Department of Molecular and Cellular Biology and Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, 77030, USA

    Rachel N. Arey

  5. Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA

    Alicia Winquist, Andrew Crain, Brian T. D. Tobe & Evan Y. Snyder

  6. Sanford Consortium for Regenerative Medicine, La Jolla, CA, 92037, USA

    Alicia Winquist, Andrew Crain, Brian T. D. Tobe & Evan Y. Snyder

  7. Department of Psychiatry, Veterans Administration Medical Center, La Jolla, CA, 92037, USA

    Brian T. D. Tobe

  8. Regenacy Pharmaceuticals, 303 Wyman St, Suite 300, Waltham, MA, 02451, USA

    Matthew B. Jarpe

  9. Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA

    Xiangning Xue, Wei Zong & George C. Tseng

  10. Department of Biostatistics, University of Florida, Gainesville, FL, 32611, USA

    Zhiguang Huo

  11. Brain and Mind Research Institute, Department of Psychiatry, and Sackler Institute for Developmental Psychobiology, Weill Cornell Medicine, New York, NY, 10021, USA

    Puja K. Parekh

  12. Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, 15260, USA

    Xiyu Zhu

  13. Peking Union Medical College Hospital, 100730, Beijing, China

    Hui Zhang

  14. Department of Pediatrics, University of California San Diego, La Jolla, CA, 92037, USA

    Evan Y. Snyder

  15. Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

    George C. Tseng

Authors
  1. Ryan W. Logan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Angela R. Ozburn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rachel N. Arey
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kyle D. Ketchesin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alicia Winquist
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andrew Crain
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Brian T. D. Tobe
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Darius Becker-Krail
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Matthew B. Jarpe
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiangning Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Wei Zong
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Zhiguang Huo
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Puja K. Parekh
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Xiyu Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Ethan Fitzgerald
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Hui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Jeffrey Oliver-Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Lauren M. DePoy
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Mariah A. Hildebrand
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Evan Y. Snyder
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. George C. Tseng
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Colleen A. McClung
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

CAM, RWL, KDK, and LMD wrote the paper. CAM, RWL, EYS, GCT, and MBJ designed experiments. RLW, ARO, RNA, AW, AC, BTDT, DB-K, MBJ, PKP, XZ, EF, HZ, JO-S, MAH, LMD, and KDK performed experiments. RWL, XX, WZ, ZH, and XZ analyzed data.

Corresponding author

Correspondence to Colleen A. McClung.

Ethics declarations

Conflict of interest

MBJ is a full type employee of Regenacy Pharmaceuticals. Studies involving the ACY compound were funded through a contract with Regenacy Pharmaceuticals Inc. to RWL. All other authors declare no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Logan, R.W., Ozburn, A.R., Arey, R.N. et al. Valproate reverses mania-like behaviors in mice via preferential targeting of HDAC2. Mol Psychiatry 26, 4066–4084 (2021). https://doi.org/10.1038/s41380-020-00958-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-020-00958-2

This article is cited by

Search

Advanced search

Quick links