Skip to main content
Log in

Serotonin in psychiatry: in vitro disease modeling using patient-derived neurons

  • Review
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Several lines of evidence implicate serotonin in the etiology of multiple psychiatric disorders, especially mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BD). Much of our current understanding of biological mechanisms underlying serotonergic alterations in mood disorders comes from animal studies. Innovation in induced pluripotent stem cell and transdifferentiation technologies for deriving neurons from adult humans has enabled the study of disease-relevant cellular phenotypes in vitro. In this context, human serotonergic neurons can now be generated using three recently published methodologies. In this mini-review, we broadly discuss evidence linking altered serotonergic neurotransmission in MDD and BD and focus on recently published methods for generating human serotonergic neurons in vitro.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Figure 1.

Similar content being viewed by others

References

  • Albert PR, Benkelfat C (2013) The neurobiology of depression--revisiting the serotonin hypothesis. II. Genetic, epigenetic and clinical studies. Philos Trans R Soc Lond B 368:20120535

    Article  Google Scholar 

  • Albert PR, Benkelfat C, Descarries L (2012) The neurobiology of depression--revisiting the serotonin hypothesis. I. Cellular and molecular mechanisms. Philos Trans R Soc Lond B 367:2378–2381

    Article  CAS  Google Scholar 

  • Artigas F (2013) Serotonin receptors involved in antidepressant effects. Pharmacol Ther 137:119–131

    Article  CAS  PubMed  Google Scholar 

  • Bansal R, Peterson BS, Gingrich J, Hao X, Odgerel Z, Warner V, Wickramaratne PJ, Talati A, Ansorge M, Brown AS, Sourander A, Weissman MM (2016) Serotonin signaling modulates the effects of familial risk for depression on cortical thickness. Psychiatry Res 248:83–93

    Article  PubMed  PubMed Central  Google Scholar 

  • Bhagwagar Z, Rabiner EA, Sargent PA, Grasby PM, Cowen PJ (2004) Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [11C]WAY-100635. Mol Psychiatry 9:386–392

    Article  CAS  PubMed  Google Scholar 

  • Bigdeli TB, Ripke S, Peterson RE, Trzaskowski M, Bacanu SA, Abdellaoui A, Andlauer TF, Beekman AT, Berger K, Blackwood DH, Boomsma DI, Breen G, Buttenschon HN, Byrne EM, Cichon S, Clarke TK, Couvy-Duchesne B, Craddock N, de Geus EJ, Degenhardt F, Dunn EC, Edwards AC, Fanous AH, Forstner AJ, Frank J, Gill M, Gordon SD, Grabe HJ, Hamilton SP, Hardiman O, Hayward C, Heath AC, Henders AK, Herms S, Hickie IB, Hoffmann P, Homuth G, Hottenga JJ, Ising M, Jansen R, Kloiber S, Knowles JA, Lang M, Li QS, Lucae S, MacIntyre DJ, Madden PA, Martin NG, McGrath PJ, McGuffin P, McIntosh AM, Medland SE, Mehta D, Middeldorp CM, Milaneschi Y, Montgomery GW, Mors O, Muller-Myhsok B, Nauck M, Nyholt DR, Nothen MM, Owen MJ, Penninx BW, Pergadia ML, Perlis RH, Peyrot WJ, Porteous DJ, Potash JB, Rice JP, Rietschel M, Riley BP, Rivera M, Schoevers R, Schulze TG, Shi J, Shyn SI, Smit JH, Smoller JW, Streit F, Strohmaier J, Teumer A, Treutlein J, Van der Auwera S, van Grootheest G, van Hemert AM, Volzke H, Webb BT, Weissman MM, Wellmann J, Willemsen G, Witt SH, Levinson DF, Lewis CM, Wray NR, Flint J, Sullivan PF, Kendler KS (2017) Genetic effects influencing risk for major depressive disorder in China and Europe. Transl Psychiatry 7:e1074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blier P, de Montigny C, Tardif D (1987) Short-term lithium treatment enhances responsiveness of postsynaptic 5-HT1A receptors without altering 5-HT autoreceptor sensitivity: an electrophysiological study in the rat brain. Synapse 1:225–232

    Article  CAS  PubMed  Google Scholar 

  • Brennand KJ, Simone A, Jou J, Gelboin-Burkhart C, Tran N, Sangar S, Li Y, Mu Y, Chen G, Yu D, McCarthy S, Sebat J, Gage FH (2011) Modelling schizophrenia using human induced pluripotent stem cells. Nature 473:221–225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Briscoe J, Sussel L, Serup P, Hartigan-O’Connor D, Jessell TM, Rubenstein JL, Ericson J (1999) Homeobox gene Nkx2.2 and specification of neuronal identity by graded sonic hedgehog signalling. Nature 398:622–627

    Article  CAS  PubMed  Google Scholar 

  • Cannon DM, Ichise M, Rollis D, Klaver JM, Gandhi SK, Charney DS, Manji HK, Drevets WC (2007) Elevated serotonin transporter binding in major depressive disorder assessed using positron emission tomography and [11C]DASB; comparison with bipolar disorder. Biol Psychiatry 62:870–877

    Article  CAS  PubMed  Google Scholar 

  • Carrard A, Salzmann A, Malafosse A, Karege F (2011) Increased DNA methylation status of the serotonin receptor 5HTR1A gene promoter in schizophrenia and bipolar disorder. J Affect Disord 132:450–453

    Article  CAS  PubMed  Google Scholar 

  • Chailangkarn T, Trujillo CA, Freitas BC, Hrvoj-Mihic B, Herai RH, Yu DX, Brown TT, Marchetto MC, Bardy C, McHenry L, Stefanacci L, Jarvinen A, Searcy YM, DeWitt M, Wong W, Lai P, Ard MC, Hanson KL, Romero S, Jacobs B, Dale AM, Dai L, Korenberg JR, Gage FH, Bellugi U, Halgren E, Semendeferi K, Muotri AR (2016) A human neurodevelopmental model for Williams syndrome. Nature 536:338–343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Charney DS (1998) Monoamine dysfunction and the pathophysiology and treatment of depression. J Clin Psychiatry 59(Suppl 14):11–14

    CAS  PubMed  Google Scholar 

  • Cho HJ, Meira-Lima I, Cordeiro Q, Michelon L, Sham P, Vallada H, Collier DA (2005) Population-based and family-based studies on the serotonin transporter gene polymorphisms and bipolar disorder: a systematic review and meta-analysis. Mol Psychiatry 10:771–781

    Article  CAS  PubMed  Google Scholar 

  • Craven SE, Lim KC, Ye W, Engel JD, de Sauvage F, Rosenthal A (2004) Gata2 specifies serotonergic neurons downstream of sonic hedgehog. Development 131:1165–1173

    Article  CAS  PubMed  Google Scholar 

  • Drevets WC, Thase ME, Moses-Kolko EL, Price J, Frank E, Kupfer DJ, Mathis C (2007) Serotonin-1A receptor imaging in recurrent depression: replication and literature review. Nucl Med Biol 34:865–877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Drysdale AT, Grosenick L, Downar J, Dunlop K, Mansouri F, Meng Y, Fetcho RN, Zebley B, Oathes DJ, Etkin A, Schatzberg AF, Sudheimer K, Keller J, Mayberg HS, Gunning FM, Alexopoulos GS, Fox MD, Pascual-Leone A, Voss HU, Casey BJ, Dubin MJ, Liston C (2017) Resting-state connectivity biomarkers define neurophysiological subtypes of depression. Nat Med 23:28–38

    Article  CAS  PubMed  Google Scholar 

  • Flint J, Kendler KS (2014) The genetics of major depression. Neuron 81:484–503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Flint J, Shifman S, Munafo M, Mott R (2008) Genetic variants in major depression. Novartis Found Symp 289:23–32 discussion 33-42, 87-93

    Article  CAS  PubMed  Google Scholar 

  • Fountoulakis KN, Gazouli M, Kelsoe J, Akiskal H (2015) The pharmacodynamic properties of lurasidone and their role in its antidepressant efficacy in bipolar disorder. Eur Neuropsychopharmacol 25:335–342

    Article  CAS  PubMed  Google Scholar 

  • Fujita M, Charney DS, Innis RB (2000) Imaging serotonergic neurotransmission in depression: hippocampal pathophysiology may mirror global brain alterations. Biol Psychiatry 48:801–812

    Article  CAS  PubMed  Google Scholar 

  • Gerhard DM, Wohleb ES, Duman RS (2016) Emerging treatment mechanisms for depression: focus on glutamate and synaptic plasticity. Drug Discov Today 21:454–464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hek K, Demirkan A, Lahti J, Terracciano A, Teumer A, Cornelis MC, Amin N, Bakshis E, Baumert J, Ding J, Liu Y, Marciante K, Meirelles O, Nalls MA, Sun YV, Vogelzangs N, Yu L, Bandinelli S, Benjamin EJ, Bennett DA, Boomsma D, Cannas A, Coker LH, de Geus E, De Jager PL, Diez-Roux AV, Purcell S, Hu FB, Rimm EB, Hunter DJ, Jensen MK, Curhan G, Rice K, Penman AD, Rotter JI, Sotoodehnia N, Emeny R, Eriksson JG, Evans DA, Ferrucci L, Fornage M, Gudnason V, Hofman A, Illig T, Kardia S, Kelly-Hayes M, Koenen K, Kraft P, Kuningas M, Massaro JM, Melzer D, Mulas A, Mulder CL, Murray A, Oostra BA, Palotie A, Penninx B, Petersmann A, Pilling LC, Psaty B, Rawal R, Reiman EM, Schulz A, Shulman JM, Singleton AB, Smith AV, Sutin AR, Uitterlinden AG, Volzke H, Widen E, Yaffe K, Zonderman AB, Cucca F, Harris T, Ladwig KH, Llewellyn DJ, Raikkonen K, Tanaka T, van Duijn CM, Grabe HJ, Launer LJ, Lunetta KL, Mosley TH Jr, Newman AB, Tiemeier H, Murabito J (2013) A genome-wide association study of depressive symptoms. Biol Psychiatry 73:667–678

    Article  CAS  PubMed  Google Scholar 

  • Heninger GR, Delgado PL, Charney DS (1996) The revised monoamine theory of depression: a modulatory role for monoamines, based on new findings from monoamine depletion experiments in humans. Pharmacopsychiatry 29:2–11

    Article  CAS  PubMed  Google Scholar 

  • Hirvonen J, Karlsson H, Kajander J, Lepola A, Markkula J, Rasi-Hakala H, Nagren K, Salminen JK, Hietala J (2008) Decreased brain serotonin 5-HT1A receptor availability in medication-naive patients with major depressive disorder: an in-vivo imaging study using PET and [carbonyl-11C]WAY-100635. Int J Neuropsychopharmacol 11:465–476

    Article  CAS  PubMed  Google Scholar 

  • Homan P, Neumeister A, Nugent AC, Charney DS, Drevets WC, Hasler G (2015) Serotonin versus catecholamine deficiency: behavioral and neural effects of experimental depletion in remitted depression. Transl Psychiatry 5:e532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hotta I, Yamawaki S, Segawa T (1986) Long-term lithium treatment causes serotonin receptor down-regulation via serotonergic presynapses in rat brain. Neuropsychobiology 16:19–26

    Article  CAS  PubMed  Google Scholar 

  • Jacob J, Ferri AL, Milton C, Prin F, Pla P, Lin W, Gavalas A, Ang SL, Briscoe J (2007) Transcriptional repression coordinates the temporal switch from motor to serotonergic neurogenesis. Nat Neurosci 10:1433–1439

    Article  CAS  PubMed  Google Scholar 

  • Ji Y, Biernacka JM, Hebbring S, Chai Y, Jenkins GD, Batzler A, Snyder KA, Drews MS, Desta Z, Flockhart D, Mushiroda T, Kubo M, Nakamura Y, Kamatani N, Schaid D, Weinshilboum RM, Mrazek DA (2013) Pharmacogenomics of selective serotonin reuptake inhibitor treatment for major depressive disorder: genome-wide associations and functional genomics. Pharmacogenom J 13:456–463

    Article  CAS  Google Scholar 

  • Kamata M, Suzuki A, Yoshida K, Takahashi H, Higuchi H, Otani K (2011) Genetic polymorphisms in the serotonergic system and symptom clusters of major depressive disorder. J Affect Disord 135:374–376

    Article  CAS  PubMed  Google Scholar 

  • Kishi T, Okochi T, Tsunoka T, Okumura T, Kitajima T, Kawashima K, Yamanouchi Y, Kinoshita Y, Naitoh H, Inada T, Kunugi H, Kato T, Yoshikawa T, Ujike H, Ozaki N, Iwata N (2011) Serotonin 1A receptor gene, schizophrenia and bipolar disorder: an association study and meta-analysis. Psychiatry Res 185:20–26

    Article  CAS  PubMed  Google Scholar 

  • Kishi T, Yoshimura R, Fukuo Y, Okochi T, Matsunaga S, Umene-Nakano W, Nakamura J, Serretti A, Correll CU, Kane JM, Iwata N (2013) The serotonin 1A receptor gene confer susceptibility to mood disorders: results from an extended meta-analysis of patients with major depression and bipolar disorder. Eur Arch Psychiatry Clin Neurosci 263:105–118

    Article  PubMed  Google Scholar 

  • Kiyasova V, Gaspar P (2011) Development of raphe serotonin neurons from specification to guidance. Eur J Neurosci 34:1553–1562

    Article  PubMed  Google Scholar 

  • Kiyasova V, Fernandez SP, Laine J, Stankovski L, Muzerelle A, Doly S, Gaspar P (2011) A genetically defined morphologically and functionally unique subset of 5-HT neurons in the mouse raphe nuclei. J Neurosci 31:2756–2768

    Article  CAS  PubMed  Google Scholar 

  • Krishnan V, Nestler EJ (2008) The molecular neurobiology of depression. Nature 455:894–902

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krishnan V, Nestler EJ (2010) Linking molecules to mood: new insight into the biology of depression. Am J Psychiatry 167:1305–1320

    Article  PubMed  PubMed Central  Google Scholar 

  • Lener MS, Niciu MJ, Ballard ED, Park M, Park LT, Nugent AC, Zarate CA Jr (2017) Glutamate and gamma-aminobutyric acid Systems in the Pathophysiology of major depression and antidepressant response to ketamine. Biol Psychiatry 81:886–897

    Article  CAS  PubMed  Google Scholar 

  • Lin SH, Lee LT, Yang YK (2014) Serotonin and mental disorders: a concise review on molecular neuroimaging evidence. Clin Psychopharmacol Neurosci 12:196–202

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu C, Deneris ES (2011) Transcriptional control of serotonin-modulated behavior and physiology. Neuropsychopharmacology 36:361–362

    Article  PubMed  Google Scholar 

  • Lu J, Zhong X, Liu H, Hao L, Huang CT, Sherafat MA, Jones J, Ayala M, Li L, Zhang SC (2016) Generation of serotonin neurons from human pluripotent stem cells. Nat Biotechnol 34:89–94

    Article  CAS  PubMed  Google Scholar 

  • Major Depressive Disorder Working Group of the Psychiatric GC, Ripke S, Wray NR, Lewis CM, Hamilton SP, Weissman MM, Breen G, Byrne EM, Blackwood DH, Boomsma DI, Cichon S, Heath AC, Holsboer F, Lucae S, Madden PA, Martin NG, McGuffin P, Muglia P, Noethen MM, Penninx BP, Pergadia ML, Potash JB, Rietschel M, Lin D, Muller-Myhsok B, Shi J, Steinberg S, Grabe HJ, Lichtenstein P, Magnusson P, Perlis RH, Preisig M, Smoller JW, Stefansson K, Uher R, Kutalik Z, Tansey KE, Teumer A, Viktorin A, Barnes MR, Bettecken T, Binder EB, Breuer R, Castro VM, Churchill SE, Coryell WH, Craddock N, Craig IW, Czamara D, De Geus EJ, Degenhardt F, Farmer AE, Fava M, Frank J, Gainer VS, Gallagher PJ, Gordon SD, Goryachev S, Gross M, Guipponi M, Henders AK, Herms S, Hickie IB, Hoefels S, Hoogendijk W, Hottenga JJ, Iosifescu DV, Ising M, Jones I, Jones L, Jung-Ying T, Knowles JA, Kohane IS, Kohli MA, Korszun A, Landen M, Lawson WB, Lewis G, Macintyre D, Maier W, Mattheisen M, McGrath PJ, McIntosh A, McLean A, Middeldorp CM, Middleton L, Montgomery GM, Murphy SN, Nauck M, Nolen WA, Nyholt DR, O’Donovan M, Oskarsson H, Pedersen N, Scheftner WA, Schulz A, Schulze TG, Shyn SI, Sigurdsson E, Slager SL, Smit JH, Stefansson H, Steffens M, Thorgeirsson T, Tozzi F, Treutlein J, Uhr M, van den Oord EJ, Van Grootheest G, Volzke H, Weilburg JB, Willemsen G, Zitman FG, Neale B, Daly M, Levinson DF, Sullivan PF (2013) A mega-analysis of genome-wide association studies for major depressive disorder. Mol Psychiatry 18:497–511

    Article  Google Scholar 

  • Marchetto MC, Belinson H, Tian Y, Freitas BC, Fu C, Vadodaria K, Beltrao-Braga PC, Trujillo CA, Mendes APD, Padmanabhan K, Nunez Y, Ou J, Ghosh H, Wright R, Brennand K, Pierce K, Eichenfield L, Pramparo T, Eyler L, Barnes CC, Courchesne E, Geschwind DH, Gage FH, Wynshaw-Boris A, Muotri AR (2017) Altered proliferation and networks in neural cells derived from idiopathic autistic individuals. Mol Psychiatry 22(6):820–835. doi:10.1038/mp.2016.95

  • Mendonca Junior FJ, Scotti L, Ishiki H, Botelho SP, Da Silva MS, Scotti MT (2015) Benzo- and thienobenzo- diazepines: multi-target drugs for CNS disorders. Mini Rev Med Chem 15:630–647

    Article  CAS  PubMed  Google Scholar 

  • Mertens J, Wang QW, Kim Y, Yu DX, Pham S, Yang B, Zheng Y, Diffenderfer KE, Zhang J, Soltani S, Eames T, Schafer ST, Boyer L, Marchetto MC, Nurnberger JI, Calabrese JR, Odegaard KJ, McCarthy MJ, Zandi PP, Alda M, Nievergelt CM, Pharmacogenomics of Bipolar Disorder S, Mi S, Brennand KJ, Kelsoe JR, Gage FH, Yao J (2015) Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature 527:95–99

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mosienko V, Beis D, Pasqualetti M, Waider J, Matthes S, Qadri F, Bader M, Alenina N (2015) Life without brain serotonin: reevaluation of serotonin function with mice deficient in brain serotonin synthesis. Behav Brain Res 277:78–88

    Article  CAS  PubMed  Google Scholar 

  • Nugent AC, Bain EE, Carlson PJ, Neumeister A, Bonne O, Carson RE, Eckelman W, Herscovitch P, Zarate CA Jr, Charney DS, Drevets WC (2013) Reduced post-synaptic serotonin type 1A receptor binding in bipolar depression. Eur Neuropsychopharmacol 23:822–829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ostergaard SD, Rothschild AJ, Flint AJ, Mulsant BH, Whyte EM, Leadholm AK, Bech P, Meyers BS (2015) Rating scales measuring the severity of psychotic depression. Acta Psychiatr Scand 132:335–344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Panchision DM (2016) Concise review: progress and challenges in using human stem cells for biological and therapeutics discovery: neuropsychiatric disorders. Stem Cells 34:523–536

    Article  PubMed  PubMed Central  Google Scholar 

  • Parr CJC, Yamanaka S, Saito H (2017) An update on stem cell biology and engineering for brain development. Mol Psychiatry 22(6):808–819. doi:10.1038/mp.2017.66

  • Pasca SP, Portmann T, Voineagu I, Yazawa M, Shcheglovitov A, Pasca AM, Cord B, Palmer TD, Chikahisa S, Nishino S, Bernstein JA, Hallmayer J, Geschwind DH, Dolmetsch RE (2011) Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat Med 17:1657–1662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Power RA, Tansey KE, Buttenschon HN, Cohen-Woods S, Bigdeli T, Hall LS, Kutalik Z, Lee SH, Ripke S, Steinberg S, Teumer A, Viktorin A, Wray NR, Arolt V, Baune BT, Boomsma DI, Borglum AD, Byrne EM, Castelao E, Craddock N, Craig IW, Dannlowski U, Deary IJ, Degenhardt F, Forstner AJ, Gordon SD, Grabe HJ, Grove J, Hamilton SP, Hayward C, Heath AC, Hocking LJ, Homuth G, Hottenga JJ, Kloiber S, Krogh J, Landen M, Lang M, Levinson DF, Lichtenstein P, Lucae S, MacIntyre DJ, Madden P, Magnusson PK, Martin NG, McIntosh AM, Middeldorp CM, Milaneschi Y, Montgomery GW, Mors O, Muller-Myhsok B, Nyholt DR, Oskarsson H, Owen MJ, Padmanabhan S, Penninx BW, Pergadia ML, Porteous DJ, Potash JB, Preisig M, Rivera M, Shi J, Shyn SI, Sigurdsson E, Smit JH, Smith BH, Stefansson H, Stefansson K, Strohmaier J, Sullivan PF, Thomson P, Thorgeirsson TE, Van der Auwera S, Weissman MM, Converge Consortium CCGC, Breen G, Lewis CM (2017) Genome-wide Association for Major Depression through age at onset stratification: major depressive disorder working Group of the Psychiatric Genomics Consortium. Biol Psychiatry 81:325–335

    Article  PubMed  PubMed Central  Google Scholar 

  • Shore PA, Pletscher A, Tomich EG, Carlsson A, Kuntzman R, Brodie BB (1957) Role of brain serotonin in reserpine action. Ann N Y Acad Sci 66:609–615 discussion, 615-607

    Article  CAS  PubMed  Google Scholar 

  • Soliman MA, Aboharb F, Zeltner N, Studer L (2017) Pluripotent stem cells in neuropsychiatric disorders. Mol Psychiatry. doi:10.1038/mp.2017.40

  • Stern S, Santos R, Marchetto MC, Mendes AP, Rouleau GA, Biesmans S, Wang QW, Yao J, Charnay P, Bang AG, Alda M, Gage FH (2017) Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients’ responsiveness to lithium. Mol Psychiatry. doi:10.1038/mp.2016.260

  • Sullivan GM, Ogden RT, Oquendo MA, Kumar JS, Simpson N, Huang YY, Mann JJ, Parsey RV (2009) Positron emission tomography quantification of serotonin-1A receptor binding in medication-free bipolar depression. Biol Psychiatry 66:223–230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Talati A, Guffanti G, Odgerel Z, Ionita-Laza I, Malm H, Sourander A, Brown AS, Wickramaratne PJ, Gingrich JA, Weissman MM (2015) Genetic variants within the serotonin transporter associated with familial risk for major depression. Psychiatry Res 228:170–173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tian Y, Voineagu I, Pasca SP, Won H, Chandran V, Horvath S, Dolmetsch RE, Geschwind DH (2014) Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome. Genome Med 6:75

    Article  PubMed  PubMed Central  Google Scholar 

  • Vadodaria KC, Marchetto MC, Mertens J, Gage FH (2016a) Generating human serotonergic neurons in vitro: methodological advances. BioEssays 38:1123–1129

    Article  CAS  PubMed  Google Scholar 

  • Vadodaria KC, Mertens J, Paquola A, Bardy C, Li X, Jappelli R, Fung L, Marchetto MC, Hamm M, Gorris M, Koch P, Gage FH (2016b) Generation of functional human serotonergic neurons from fibroblasts. Mol Psychiatry 21:49–61

    Article  CAS  PubMed  Google Scholar 

  • Vallstedt A, Muhr J, Pattyn A, Pierani A, Mendelsohn M, Sander M, Jessell TM, Ericson J (2001) Different levels of repressor activity assign redundant and specific roles to Nkx6 genes in motor neuron and interneuron specification. Neuron 31:743–755

    Article  CAS  PubMed  Google Scholar 

  • Wen Z, Nguyen HN, Guo Z, Lalli MA, Wang X, Su Y, Kim NS, Yoon KJ, Shin J, Zhang C, Makri G, Nauen D, Yu H, Guzman E, Chiang CH, Yoritomo N, Kaibuchi K, Zou J, Christian KM, Cheng L, Ross CA, Margolis RL, Chen G, Kosik KS, Song H, Ming GL (2014) Synaptic dysregulation in a human iPS cell model of mental disorders. Nature 515:414–418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu Z, Jiang H, Zhong P, Yan Z, Chen S, Feng J (2016) Direct conversion of human fibroblasts to induced serotonergic neurons. Mol Psychiatry 21:62–70

    Article  CAS  PubMed  Google Scholar 

  • Yi F, Danko T, Botelho SC, Patzke C, Pak C, Wernig M, Sudhof TC (2016) Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons. Science 352:aaf2669

NIMH data references

Download references

Acknowledgements

This work has been supported by the Swiss National Science Foundation (PD outgoing fellowship, K.C.V.), the Lynn and Edward Streim fellowship (K.C.V.), Takeda-Sanford Innovation Allianc e Grant, the Paul G. Allen Family Foundation, Bob and Mary Jane Engman, The JPB Foundation, The Leona M. and Harry B. Helmsley Charitable Trust grant #2012-PG-MED002, Annette C. Merle-Smith and NIMH grant U19MH106434. The authors would like to thank M.L. Gage for editorial comments.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Fred H. Gage.

Ethics declarations

Conflict of interest

The authors declare no conflict of interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vadodaria, K.C., Stern, S., Marchetto, M.C. et al. Serotonin in psychiatry: in vitro disease modeling using patient-derived neurons. Cell Tissue Res 371, 161–170 (2018). https://doi.org/10.1007/s00441-017-2670-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-017-2670-4

Keywords

Navigation