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Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients

Molecular Psychiatry volume 26, pages 2440–2456 (2021)Cite this article

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Abstract

Bipolar disorder (BD) is a psychiatric condition characterized by depressive and manic episodes that affect 2% of the world population. The first-line long-term treatment for mood stabilization is lithium (Li). Induced pluripotent stem cell modeling of BD using hippocampal dentate gyrus-like neurons derived from Li-responsive (LR) and Li-non-responsive (NR) patients previously showed neuronal hyperexcitability. Li treatment reversed hyperexcitability only on the LR neurons. In this study we searched for specific targets of Li resistance in NR neurons and found that the activity of Wnt/β-catenin signaling pathway was severely affected, with a significant decrease in expression of LEF1. Li targets the Wnt/β-catenin signaling pathway by inhibiting GSK-3β and releasing β-catenin that forms a nuclear complex with TCF/LEF1, activating the Wnt/β-catenin transcription program. Therefore, we propose that downregulation of LEF1 may account for Li resistance in NR neurons. Our results show that valproic acid (VPA), a drug used to treat NR patients that also acts downstream of GSK-3β, upregulated LEF1 and Wnt/β-catenin gene targets, increased transcriptional activity of complex β-catenin/TCF/LEF1, and reduced excitability in NR neurons. In addition, decreasing LEF1 expression in control neurons using shLEF1 caused hyperexcitability, confirming that the impact of VPA on excitability in NR neurons was connected to changes in LEF1 and in the Wnt/β-catenin pathway. Our results suggest that LEF1 may be a useful target for the discovery of new drugs for BD treatment.

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Fig. 1: NR neurons became transcriptionally distinct during differentiation.
Fig. 2: Dysregulation of Wnt/β-catenin signaling in NR neurons.
Fig. 3: Downregulation of LEF1 gene and Wnt/β-catenin signaling impairment in NR neurons.
Fig. 4: VPA increases Wnt/β-catenin signaling and induces LEF1 expression.
Fig. 5: Hyperexcitability is modulated by VPA and LEF1 expression.
Fig. 6: Model of action of Li and VPA on LEF1 expression and hyperexcitability in NR neurons.

Data availability

GEO Accession number is GSE159487.

References

  1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, fifth edition. Washington, DC: American Psychiatric Press, Inc.; 2013.

  2. WHO. The ICD-10 classification of mental and behavioural disorders: diagnostic criteria for research. Geneva: World Health Organization; 1993.

  3. Vieta E, Berk M, Schulze TG, Carvalho AF, Suppes T, Calabrese JR, et al. Bipolar disorders. Nat Rev Dis Prim. 2018;4:18008.

    Article  PubMed  Google Scholar 

  4. Angst J, Gamma A. A new bipolar spectrum concept: a brief review. Bipolar Disord. 2002;4:11–4.

    Article  PubMed  Google Scholar 

  5. Merikangas KR, Jin R, He JP, Kessler RC, Lee S, Sampson NA, et al. Prevalence and correlates of bipolar spectrum disorder in the World Mental Health Survey Initiative. Arch Gen Psychiatry. 2011;68:241–51.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Hede V, Favre S, Aubry JM, Richard-Lepouriel H. Bipolar spectrum disorder: what evidence for pharmacological treatment? A systematic review. Psychiatry Res. 2019;282:112627.

    Article  PubMed  Google Scholar 

  7. Phillips ML, Kupfer DJ. Bipolar disorder diagnosis: challenges and future directions. Lancet. 2013;381:1663–71.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Fritz K, Russell AMT, Allwang C, Kuiper S, Lampe L, Malhi GS. Is a delay in the diagnosis of bipolar disorder inevitable? Bipolar Disord. 2017;19:396–400.

    Article  PubMed  Google Scholar 

  9. Alonso J, Petukhova M, Vilagut G, Chatterji S, Heeringa S, Üstün TB, et al. Days out of role due to common physical and mental conditions: results from the WHO World Mental Health Surveys. Mol Psychiatry. 2011;16:1234–46.

    Article  CAS  PubMed  Google Scholar 

  10. Alda M. Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics. Mol Psychiatry. 2015;20:661–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Miller JN, Black DW. Bipolar disorder and suicide: a review. Curr Psychiatry Rep. 2020;22:6.

    Article  PubMed  Google Scholar 

  12. Harrison PJ, Cipriani A, Harmer CJ, Nobre AC, Saunders K, Goodwin GM, et al. Innovative approaches to bipolar disorder and its treatment. Ann N Y Acad Sci. 2016;1366:76–89.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Ahrens B, Müller-Oerlinghausen B, Grof P. Length of lithium treatment needed to eliminate the high mortality of affective disorders. Br J Psychiatry Suppl. 1993;21:27–29.

    Article  Google Scholar 

  14. Scott J, Hidalgo-Mazzei D, Strawbridge R, Young A, Resche-Rigon M, Etain B, et al. Prospective cohort study of early biosignatures of response to lithium in bipolar-I-disorders: overview of the H2020-funded R-LiNK initiative. Int J Bipolar Disord. 2019;7:20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Hui TP, Kandola A, Shen L, Lewis G, Osborn DPJ, Geddes JR, et al. A systematic review and meta-analysis of clinical predictors of lithium response in bipolar disorder. Acta Psychiat Scand. 2019;140:94–115.

    Article  CAS  PubMed  Google Scholar 

  16. Hunsberger JG, Chibane FL, Elkahloun AG, Henderson R, Singh R, Lawson J, et al. Novel integrative genomic tool for interrogating lithium response in bipolar disorder. Transl Psychiatry. 2015;5:e504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Tondo L, Alda M, Bauer M, Bergink V, Grof P, Hajek T, et al. Clinical use of lithium salts: guide for users and prescribers. Int J Bipolar Disord. 2019;7:16.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Tournier M, Neumann A, Pambrun E, Weil A, Chaffiol JP, Alla F, et al. Conventional mood stabilizers and/or second-generation antipsychotic drugs in bipolar disorders: a population-based comparison of risk of treatment failure. J Affect Disord. 2019;257:412–20.

    Article  PubMed  Google Scholar 

  19. Cipriani A, Barbui C, Salanti G, Rendell J, Brown R, Stockton ST, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet. 2011;378:1306–15.

    Article  CAS  PubMed  Google Scholar 

  20. Tibrewal P, Ng T, Bastiampillai T, Dhillon R, Koh DH, Kulkarni S. Why is lithium use declining? Asian J Psychiatr. 2019;43:219–20.

    Article  PubMed  Google Scholar 

  21. National Collaborating Centre for Mental Health (UK). Bipolar disorder: the NICE guideline on the assessment and management of bipolar disorder in adults, children and young people in primary and secondary care. London: The British Psychological Society and The Royal College of Psychiatrists; 2014.

    Google Scholar 

  22. Goodwin GM, Haddad PM, Ferrier IN, Aronson JK, Barnes T, Cipriani A, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2016;30:495–553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Won E, Kim YK. An oldie but goodie: lithium in the treatment of bipolar disorder through neuroprotective and neurotrophic mechanisms. Int J Mol Sci. 2017;18:2679.

    Article  PubMed Central  CAS  Google Scholar 

  24. Weinstock LM, Gaudiano BA, Epstein-Lubow G, Tezanos K, Celis-deHoyos CE, Miller IW. Medication burden in bipolar disorder: a chart review of patients at psychiatric hospital admission. Psychiatry Res. 2014;216:24–30.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Jope RS. Lithium and GSK-3: one inhibitor, two inhibitory actions, multiple outcomes. Trends Pharm Sci. 2003;24:441–3.

    Article  CAS  PubMed  Google Scholar 

  26. Butler-Munro C, Coddington EJ, Shirley CH, Heyward PM. Lithium modulates cortical excitability in vitro. Brain Res. 2010;1352:50–60.

    Article  CAS  PubMed  Google Scholar 

  27. Tselnicker IF, Tsemakhovich V, Rishal I, Kahanovitch U, Dessauer CW, Dascal N. Dual regulation of G proteins and the G-protein-activated K+ channels by lithium. Proc Natl Acad Sci U S A. 2014;111:5018–23.

    Article  CAS  Google Scholar 

  28. Bachmann RF, Wang Y, Yuan P, Zhou R, Li X, Alesci S, et al. Common effects of lithium and valproate on mitochondrial functions: protection against methamphetamine-induced mitochondrial damage. Int J Neuropsychopharmacol. 2009;12:805–22.

    Article  CAS  PubMed  Google Scholar 

  29. Roux M, Dosseto A. From direct to indirect lithium targets: a comprehensive review of omics data. Metallomics. 2017;9:1326–51.

    Article  CAS  PubMed  Google Scholar 

  30. Maurer IC, Schippel P, Volz H-P. Lithium-induced enhancement of mitochondrial oxidative phosphorylation in human brain tissue. Bipolar Disord. 2009;11:515–22.

    Article  CAS  PubMed  Google Scholar 

  31. Bellivier F, Marie-Claire C. Molecular signatures of lithium treatment: current knowledge. Pharmacopsychiatry. 2018;51:212–9.

    Article  CAS  PubMed  Google Scholar 

  32. Kidnapillai S, Wade B, Bortolasci CC, Panizzutti B, Spolding B, Connor T, et al. Drugs used to treat bipolar disorder act via microRNAs to regulate expression of genes involved in neurite outgrowth. J Psychopharmacol. 2020;34:370–9.

    Article  CAS  PubMed  Google Scholar 

  33. Stamos JL, Weis WI. The β-catenin destruction complex. Cold Spring Harb Perspect Biol. 2013;5:a007898.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Cadigan KM, Waterman ML. TCF/LEFs and Wnt signaling in the nucleus. Cold Spring Harb Perspect Biol. 2012;4:a007906.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Pérez-Palma E, Andrade V, Caracci MO, Bustos BI, Villaman C, Medina MA, et al. Early transcriptional changes induced by Wnt/β-catenin signaling in hippocampal neurons. Neural Plast. 2016;2016:4672841.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Gupta A, Schulze TG, Nagarajan V, Akula N, Corona W, Jiang XY, et al. Interaction networks of lithium and valproate molecular targets reveal a striking enrichment of apoptosis functional clusters and neurotrophin signaling. Pharmacogenomics J. 2012;12:328–41.

    Article  CAS  PubMed  Google Scholar 

  37. 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.

    Article  CAS  PubMed  Google Scholar 

  38. Hoseth EZ, Krull F, Dieset I, Morch RH, Hope S, Gardsjord ES, et al. Exploring the Wnt signaling pathway in schizophrenia and bipolar disorder. Transl Psychiatry. 2018;8:55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Pandey GN, Rizavi HS, Tripathi M, Ren X. Region-specific dysregulation of glycogen synthase kinase-3β and β-catenin in the postmortem brains of subjects with bipolar disorder and schizophrenia. Bipolar Disord. 2015;17:160–71.

    Article  CAS  PubMed  Google Scholar 

  40. Wang M, Zhang L, Gage FH. Modeling neuropsychiatric disorders using human induced pluripotent stem cells. Protein Cell. 2020;11:45–59.

    Article  CAS  PubMed  Google Scholar 

  41. Craddock N, Sklar P. Genetics of bipolar disorder. Lancet. 2013;381:1654–62.

    Article  CAS  PubMed  Google Scholar 

  42. Miller ND, Kelsoe JR. Unraveling the biology of bipolar disorder using induced pluripotent stem-derived neurons. Bipolar Disord. 2017;19:544–51.

    Article  PubMed  PubMed Central  Google Scholar 

  43. 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;23:1453–69.

    Article  CAS  PubMed  Google Scholar 

  44. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Stern S, Sarkar A, Stern T, Mei A, Mendes APD, Stern Y, et al. Mechanisms underlying the hyperexcitability of CA3 and dentate gyrus hippocampal neurons derived from patients with bipolar disorder. Biol Psychiatry. 2020;8:139–49.

    Article  CAS  Google Scholar 

  46. Wang JL, Shamah SM, Sun AX, Waldman ID, Haggarty SJ, Perlis RH. Label-free, live optical imaging of reprogrammed bipolar disorder patient-derived cells reveals a functional correlate of lithium responsiveness. Transl Psychiatry. 2014;4:e428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bardy C, van den Hurk M, Eames T, Marchand C, Hernandez RV, Kellogg M, et al. Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro. Proc Natl Acad Sci U S A. 2015;112:E2725–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Endicott J, Spitzer RL. A diagnostic interview: the schedule for affective disorders and schizophrenia. Arch Gen Psychiatry. 1978;35:837–44.

    Article  CAS  PubMed  Google Scholar 

  49. Grof P, Duffy A, Cavazzoni P, Grof E, Garnham J, MacDougall M, et al. Is response to prophylactic lithium a familial trait? J Clin Psychiatry. 2002;63:942–7.

    Article  CAS  PubMed  Google Scholar 

  50. Manchia M, Adli M, Akula N, Ardau R, Aubry JM, Backlund L, et al. Assessment of response to lithium maintenance treatment in bipolar disorder: a Consortium on Lithium Genetics (ConLiGen) report. PLoS ONE. 2013;8:e65636.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Yu DX, Di Giorgio FP, Yao J, Marchetto MC, Brennand K, Wright R, et al. Modeling hippocampal neurogenesis using human pluripotent stem cells. Stem Cell Rep. 2014;2:295–310.

    Article  CAS  Google Scholar 

  52. Fuerer C, Nusse R. Lentiviral vectors to probe and manipulate the Wnt signaling pathway. PLoS ONE. 2010;5:e9370.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Andrews S. FastQC: a quality control tool for high throughput sequence data. 2010. in Reference Source.

  54. Cox MP, Peterson DA, Biggs PJ. SolexaQA: at-a-glance quality assessment of Illumina second-generation sequencing data. BMC Bioinform. 2010;11:485.

    Article  Google Scholar 

  55. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.

    Article  CAS  PubMed  Google Scholar 

  56. Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26:139–40.

    Article  CAS  PubMed  Google Scholar 

  57. Huang DW, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4:44–57.

    Article  CAS  Google Scholar 

  58. Huang DW, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2009;37:1–13.

    Article  CAS  Google Scholar 

  59. Matys V, Kel-Margoulis OV, Fricke E, Liebich I, Land S, Barre-Dirrie A, et al. TRANSFAC and its module TRANSCompel: transcriptional gene regulation in eukaryotes. Nucleic Acids Res. 2006;34:D108–10.

    Article  CAS  PubMed  Google Scholar 

  60. Iwano T, Masuda A, Kiyonari H, Enomoto H, Matsuzu F. Prox1 postmitotically defines dentate gyrus cells by specifying granule cell identity over CA3 pyramidal cell fate in the hippocampus. Development. 2012;139:3051–62.

    Article  CAS  PubMed  Google Scholar 

  61. Lavado A, Lagutin OV, Chow LM, Baker SJ, Oliver G. Prox1 is required for granule cell maturation and intermediate progenitor maintenance during brain neurogenesis. PLoS Biol. 2010;8:e1000460.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Krejci P, Aklian A, Kaucka M, Sevcikova E, Prochazkova J, Masek JK, et al. Receptor tyrosine kinases activate canonical WNT/β-catenin signaling via MAP kinase/LRP6 pathway and direct β-catenin phosphorylation. PLoS ONE. 2012;7:e35826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Hu Y, Chen W, Wu L, Jiang L, Liang N, Tan L, et al. TGF-β1 restores hippocampal synaptic plasticity and memory in Alzheimer model via the PI3K/Akt/Wnt/β-Catenin signaling pathway. J Mol Neurosci. 2019;67:142–9.

    Article  CAS  PubMed  Google Scholar 

  64. Falk S, Wurdak H, Ittner LM, Ille F, Sumara G, Schmid MT, et al. Brain area-specific effect of TGF-β signaling on Wnt-dependent neural stem cell expansion. Cell Stem Cell. 2008;2:472–83.

    Article  CAS  PubMed  Google Scholar 

  65. Ying L, Mills JA, French DL, Gadue P. OCT4 coordinates with WNT signaling to pre-pattern chromatin at the SOX17 locus during human ES cell differentiation into definitive endoderm. Stem Cell Rep. 2015;5:490–8.

    Article  CAS  Google Scholar 

  66. Agathocleous M, Iordanova I, Willardsen MI, Xue XY, Vetter ML, Harris WA, et al. A directional Wnt/β-catenin-Sox2-proneural pathway regulates the transition from proliferation to differentiation in the Xenopus retina. Development. 2009;136:3289–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Arredondo SB, Guerrero FG, Herrera-Soto A, Jensen-Flores J, Bustamante DB, Oñate-Ponce A, et al. Wnt5a promotes differentiation and development of adult-born neurons in the hippocampus by noncanonical Wnt signaling. Stem Cells. 2020;38:422–36.

    Article  CAS  PubMed  Google Scholar 

  68. Schafer ST, Han J, Pena M, von Bohlen Und Halbach O, Peters J, Gage FH. The Wnt adaptor protein ATP6AP2 regulates multiple stages of adult hippocampal neurogenesis. J Neurosci. 2015;35:4983–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Armenteros T, Andreu Z, Hortigüela R, Lie DC, Mira H. BMP and WNT signalling cooperate through LEF1 in the neuronal specification of adult hippocampal neural stem and progenitor cells. Sci Rep. 2018;8:9241.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Zhang X, Bertaso F, Yoo JW, Baumgärtel K, Clancy SM, Lee V, et al. Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy. Nat Neurosci. 2010;13:1056–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Atacho DAM, Reynisson H, Petursdottir AT, Eysteinsson T, Steingrimsson E, Petersen PH. Mitf links neuronal activity and long-term homeostatic intrinsic plasticity. eNeuro. 2020;7:ENEURO.0412-19.2020.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Chiu CT, Wang Z, Hunsberger JG, Chuang DM. Therapeutic potential of mood stabilizers lithium and valproic acid: beyond bipolar disorder. Pharm Rev. 2012;65:105–42.

    Article  CAS  Google Scholar 

  73. Berg DA, Su Y, Jimenez-Cyrus D, Patel A, Huang N, Morizet D, et al. A common embryonic origin of stem cells drives developmental and adult neurogenesis. Cell. 2019;177:654–68.e15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Rimol LM, Hartberg CB, Nesvåg R, Fennema-Notestine C, Hagler DJ Jr, Pung CJ, et al. Cortical thickness and subcortical volumes in schizophrenia and bipolar disorder. Biol Psychiatry. 2010;68:41–50.

    Article  PubMed  Google Scholar 

  75. Haukvik UK, Westlye LT, Mørch-Johnsen L, Jørgensen KN, Lange EH, Dale AM, et al. In vivo hippocampal subfield volumes in schizophrenia and bipolar disorder. Biol Psychiatry. 2015;77:581–8.

    Article  PubMed  Google Scholar 

  76. Hajek T, Bauer M, Simhandl C, Rybakowski J, O’Donovan C, Pfennig A, et al. Neuroprotective effect of lithium on hippocampal volumes in bipolar disorder independent of long-term treatment response. Psychol Med. 2014;44:507–17.

    Article  CAS  PubMed  Google Scholar 

  77. Otten M, Meeter M. Hippocampal structure and function in Individuals with bipolar disorder: a systematic review. J Affect Disord. 2015;174:113–25.

    Article  PubMed  Google Scholar 

  78. Han KM, Kim A, Kang W, Kang Y, Kang J, Won E, et al. Hippocampal subfield volumes in major depressive disorder and bipolar disorder. Eur Psychiatry. 2019;57:70–7.

    Article  PubMed  Google Scholar 

  79. Simonetti A, Sani G, Dacquino C, Piras F, De Rossi P, Caltagirone C, et al. Hippocampal subfield volumes in short- and long-term lithium-treated patients with bipolar I disorder. Bipolar Disord. 2016;18:352–62.

    Article  CAS  PubMed  Google Scholar 

  80. Cao B, Passos IC, Mwangi B, Amaral-Silva H, Tannous J, Wu MJ, et al. Hippocampal subfield volumes in mood disorders. Mol Psychiatry. 2017;22:1352–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Lie DC, Colamarino SA, Song HJ, Désiré L, Mira H, Consiglio A, et al. Wnt signalling regulates adult hippocampal neurogenesis. Nature. 2005;437:1370–5.

    Article  CAS  PubMed  Google Scholar 

  82. Lee SM, Tole S, Grove E, McMahon AP. A Local Wnt-3a signal is required for development of the mammalian hippocampus. Development. 2000;127:457–67.

    Article  CAS  PubMed  Google Scholar 

  83. Galceran J, Miyashita-Lin EM, Devaney E, Rubenstein JL, Grosschedl R. Hippocampus development and generation of dentate gyrus granule cells is regulated by LEF1. Development. 2000;127:469–82.

    Article  CAS  PubMed  Google Scholar 

  84. Zhou CJ, Zhao C, Pleasure SJ. Wnt signaling mutants have decreased dentate granule cell production and radial glial scaffolding abnormalities. J Neurosci. 2004;24:121–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Karalay Ö, Doberauer K, Vadodaria KC, Knobloch M, Berti L, Miquelajauregui A, et al. Prospero-related homeobox 1 gene (Prox1) is regulated by canonical Wnt signaling and has a stage-specific role in adult hippocampal neurogenesis. Proc Natl Acad Sci U S A. 2011;108:5807–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 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 U S A. 2007;104:10164–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kloiber S, Rosenblat JD, Husain MI, Ortiz A, Berk M, Quevedo J, et al. Neurodevelopmental pathways in bipolar disorder. Neurosci Biobehav Rev. 2020;112:213–26.

    Article  PubMed  Google Scholar 

  88. O’Shea KS, McInnis MG. Neurodevelopmental origins of bipolar disorder: iPSC models. Mol Cell Neurosci. 2016;73:63–83.

    Article  PubMed  CAS  Google Scholar 

  89. Hagihara H, Takao K, Walton NM, Matsumoto M, Miyakawa T. Immature dentate gyrus: an endophenotype of neuropsychiatric disorders. Neural Plast. 2013;2013:318596.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Walton NM, Zhou Y, Kogan JH, Shin R, Webster M, Gross AK, et al. Detection of an immature dentate gyrus feature in human schizophrenia/bipolar patients. Transl Psychiatry. 2012;2:e135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. McQuate A, Latorre-Esteves E, Barria A. A Wnt/calcium signaling cascade regulates neuronal excitability and trafficking of NMDARs. Cell Rep. 2017;21:60–69.

    Article  CAS  PubMed  Google Scholar 

  92. Ciani L, Boyle KA, Dickins E, Sahores M, Anane D, Lopes DM, et al. Wnt7a signaling promotes dendritic spine growth and synaptic strength through Ca2+/Calmodulin-dependent protein kinase II. Proc Natl Acad Sci U S A. 2011;108:10732–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Sahores M, Gibb A, Salinas PC. Frizzled-5, a receptor for the synaptic organizer Wnt7a, regulates activity-mediated synaptogenesis. Development. 2010;137:2215–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Davis EK, Zou Y, Ghosh A. Wnts acting through canonical and noncanonical signaling pathways exert opposite effects on hippocampal synapse formation. Neural Dev. 2008;3:32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Parodi J, Montecinos-Oliva C, Varas R, Alfaro IE, Serrano FG, Varas-Godoy M, et al. Wnt5a inhibits K+ currents in hippocampal synapses through nitric oxide production. Mol Cell Neurosci. 2015;68:314–22.

    Article  CAS  PubMed  Google Scholar 

  96. Oliva CA, Inestrosa NC. A novel function for Wnt signaling modulating neuronal firing activity and the temporal structure of spontaneous oscillation in the entorhinal-hippocampal circuit. Exp Neurol. 2015;269:43–55.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the Salk Institute Core Facilities: Next Generation Sequencing (NGS) Core Facility with funding from NIH-NCI CCSG: P30 014195, the Chapman Foundation and the Helmsley Charitable Trust; The Razavi Newman Integrative Genomics and Bioinformatics Core Facility with funding from NIH-NCI CCSG: P30 014195; and Flow Cytometry Core Facility with funding from NIH-NCI CCSG: P30 014195. We would also like to thank M.L. Gage for editorial comments. This work was supported by the National Cancer Institute (Grant No. P30 CA014195) and the National Institutes of Health (Grant No. R01AG05651) and by the National Cooperative Reprogrammed Cell Research Groups (NCRCRG; Grant No. U19 MH106434). The Gage laboratory is supported in part by the JPB Foundation, Annette C. Merle-Smith, and the Robert and Mary Jane Engman Foundation. SS acknowledges Zuckerman STEM leadership program funding.

Author information

Author notes

  1. These authors contributed equally: Renata Santos, Sara B. Linker, Shani Stern

  2. These authors jointly supervised this work: Maria C. Marchetto, Fred H. Gage

Authors and Affiliations

  1. Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Renata Santos, Sara B. Linker, Shani Stern, Ana P. D. Mendes, Lynne Randolph-Moore, Vipula Racha, Yeni Kim, Maria C. Marchetto & Fred H. Gage

  2. University of Paris, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Laboratory of Dynamics of Neuronal Structure in Health and Disease, 102 Rue de la Santé, 75014, Paris, France

    Renata Santos

  3. Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, 3498838, Israel

    Shani Stern

  4. The Razavi Newman Integrative Genomics and Bioinformatics Core (IGC), The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Maxim N. Shokhirev & Galina Erikson

  5. Department of Psychiatry, Dongguk University International Hospital, 27 Donggukro Ilsandonggu, 10326, Goyang, South Korea

    Yeni Kim

  6. Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093, USA

    John R. Kelsoe

  7. Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Anne G. Bang

  8. Department of Psychiatry, Dalhousie University, 5909 Veterans’ Memorial Lane, Halifax, NS, B3H 2E2, Canada

    M. Alda

  9. Department of Anthropology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA

    Maria C. Marchetto

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  1. Renata Santos
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  2. Sara B. Linker
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  3. Shani Stern
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Correspondence to Renata Santos, Maria C. Marchetto or Fred H. Gage.

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Santos, R., Linker, S.B., Stern, S. et al. Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients. Mol Psychiatry 26, 2440–2456 (2021). https://doi.org/10.1038/s41380-020-00981-3

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