Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
04 May 2024
04 May 2024
Historique:
received:
17
05
2022
accepted:
12
04
2024
revised:
01
04
2024
medline:
5
5
2024
pubmed:
5
5
2024
entrez:
4
5
2024
Statut:
aheadofprint
Résumé
Schizophrenia affects approximately 1% of the world population. Genetics, epigenetics, and environmental factors are known to play a role in this psychiatric disorder. While there is a high concordance in monozygotic twins, about half of twin pairs are discordant for schizophrenia. To address the question of how and when concordance in monozygotic twins occur, we have obtained fibroblasts from two pairs of schizophrenia discordant twins (one sibling with schizophrenia while the second one is unaffected by schizophrenia) and three pairs of healthy twins (both of the siblings are healthy). We have prepared iPSC models for these 3 groups of patients with schizophrenia, unaffected co-twins, and the healthy twins. When the study started the co-twins were considered healthy and unaffected but both the co-twins were later diagnosed with a depressive disorder. The reprogrammed iPSCs were differentiated into hippocampal neurons to measure the neurophysiological abnormalities in the patients. We found that the neurons derived from the schizophrenia patients were less arborized, were hypoexcitable with immature spike features, and exhibited a significant reduction in synaptic activity with dysregulation in synapse-related genes. Interestingly, the neurons derived from the co-twin siblings who did not have schizophrenia formed another distinct group that was different from the neurons in the group of the affected twin siblings but also different from the neurons in the group of the control twins. Importantly, their synaptic activity was not affected. Our measurements that were obtained from schizophrenia patients and their monozygotic twin and compared also to control healthy twins point to hippocampal synaptic deficits as a central mechanism in schizophrenia.
Identifiants
pubmed: 38704507
doi: 10.1038/s41380-024-02561-1
pii: 10.1038/s41380-024-02561-1
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Israel Science Foundation (ISF)
ID : 3252/21
Informations de copyright
© 2024. The Author(s).
Références
Bhugra D. The global prevalence of schizophrenia. PLoS Med. 2005;2:e151.
pubmed: 15916460
pmcid: 1140960
doi: 10.1371/journal.pmed.0020151
Haro JM, Novick D, Bertsch J, Karagianis J, Dossenbach M, Jones PB. Cross-national clinical and functional remission rates: Worldwide Schizophrenia Outpatient Health Outcomes (W-SOHO) study. Br J Psychiatry. 2011;199:194–201.
pubmed: 21881098
doi: 10.1192/bjp.bp.110.082065
Saha S, Chant D, Welham J, McGrath J. A systematic review of the prevalence of schizophrenia. PLoS Med. 2005;2:e141.
pubmed: 15916472
pmcid: 1140952
doi: 10.1371/journal.pmed.0020141
Wright IC, Rabe-Hesketh S, Woodruff PW, David AS, Murray RM, Bullmore ET. Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry. 2000;157:16–25.
pubmed: 10618008
doi: 10.1176/ajp.157.1.16
Tamminga CA, Stan AD, Wagner AD. The hippocampal formation in schizophrenia. Am J Psychiatry. 2010;167:1178–93.
pubmed: 20810471
doi: 10.1176/appi.ajp.2010.09081187
Ellison-Wright I, Bullmore E. Meta-analysis of diffusion tensor imaging studies in schizophrenia. Schizophr Res. 2009;108:3–10.
pubmed: 19128945
doi: 10.1016/j.schres.2008.11.021
Coyle JT. The glutamatergic dysfunction hypothesis for schizophrenia. Harv Rev Psychiatry. 1996;3:241–53.
pubmed: 9384954
doi: 10.3109/10673229609017192
Cioffi CL. Modulation of NMDA receptor function as a treatment for schizophrenia. Bioorg Med Chem Lett. 2013;23:5034–44.
pubmed: 23916256
doi: 10.1016/j.bmcl.2013.07.019
Brisch R, Saniotis A, Wolf R, Bielau H, Bernstein HG, Steiner J, et al. The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: old fashioned, but still in vogue. Front Psychiatry. 2014;5:47.
pubmed: 24904434
pmcid: 4032934
Balu DT. The NMDA receptor and schizophrenia: from pathophysiology to treatment. Adv Pharmacol. 2016;76:351–82.
pubmed: 27288082
pmcid: 5518924
doi: 10.1016/bs.apha.2016.01.006
Vilain J, Galliot AM, Durand-Roger J, Leboyer M, Llorca PM, Schurhoff F, et al. [Environmental risk factors for schizophrenia: a review]. Encephale. 2013;39:19–28.
pubmed: 23177330
doi: 10.1016/j.encep.2011.12.007
Narayan CL, Shikha D, Shekhar S. Schizophrenia in identical twins. Indian J Psychiatry. 2015;57:323–4.
pubmed: 26600594
pmcid: 4623659
doi: 10.4103/0019-5545.166635
Hilker R, Helenius D, Fagerlund B, Skytthe A, Christensen K, Werge TM, et al. Heritability of schizophrenia and schizophrenia spectrum based on the nationwide Danish twin register. Biol Psychiatry. 2018;83:492–8.
pubmed: 28987712
doi: 10.1016/j.biopsych.2017.08.017
Cardno AG, Gottesman II. Twin studies of schizophrenia: from bow-and-arrow concordances to Star Wars Mx and functional genomics. Am J Med Genet. 2000;97:12–7.
pubmed: 10813800
doi: 10.1002/(SICI)1096-8628(200021)97:1<12::AID-AJMG3>3.0.CO;2-U
Dennison CA, Legge SE, Pardinas AF, Walters JTR. Genome-wide association studies in schizophrenia: Recent advances, challenges and future perspective. Schizophr Res. 2020;217:4–12.
pubmed: 31780348
doi: 10.1016/j.schres.2019.10.048
Ripke S, O’Dushlaine C, Chambert K, Moran JL, Kahler AK, Akterin S, et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet. 2013;45:1150–9.
pubmed: 23974872
pmcid: 3827979
doi: 10.1038/ng.2742
Schizophrenia Working Group of the Psychiatric Genomics C. Biological insights from 108 schizophrenia- associated genetic loci. Nature. 2014;511:421–7.
doi: 10.1038/nature13595
Schmidt-Kastner R, Guloksuz S, Kietzmann T, van Os J, Rutten BPF. Analysis of GWAS-derived schizophrenia genes for links to ischemia-hypoxia response of the brain. Front Psychiatry. 2020;11:393.
pubmed: 32477182
pmcid: 7235330
doi: 10.3389/fpsyt.2020.00393
Choudhary A, Peles D, Nayak R, Mizrahi L, Stern S. Current progress in understanding schizophrenia using genomics and pluripotent stem cells: a meta-analytical overview. Schizophr Res. 2022.
Romanovsky E, Choudhary A, Abu Akel A, Stern S. Seeking convergence and divergence between autism and schizophrenia using genomic tools and patients’ neurons. Preprint at https://doi.org/10.1101/2023.08.11.552921 .
Lam M, Chen CY, Li Z, Martin AR, Bryois J, Ma X, et al. Comparative genetic architectures of schizophrenia in East Asian and European populations. Nat Genet. 2019;51:1670–8.
pubmed: 31740837
pmcid: 6885121
doi: 10.1038/s41588-019-0512-x
Huo Y, Li S, Liu J, Li X, Luo XJ. Functional genomics reveal gene regulatory mechanisms underlying schizophrenia risk. Nat Commun. 2019;10:670.
pubmed: 30737407
pmcid: 6368563
doi: 10.1038/s41467-019-08666-4
Thyme SB, Pieper LM, Li EH, Pandey S, Wang Y, Morris NS, et al. Phenotypic landscape of schizophrenia- associated genes defines candidates and their shared functions. Cell. 2019;177:478–91. e20.
pubmed: 30929901
pmcid: 6494450
doi: 10.1016/j.cell.2019.01.048
Rajarajan P, Borrman T, Liao W, Schrode N, Flaherty E, Casino C, et al. Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk. Science. 2018;362:eaat4311.
pubmed: 30545851
pmcid: 6408958
doi: 10.1126/science.aat4311
He D, Fan C, Qi M, Yang Y, Cooper DN, Zhao H. Prioritization of schizophrenia risk genes from GWAS results by integrating multi-omics data. Transl Psychiatry. 2021;11:175.
pubmed: 33731678
pmcid: 7969765
doi: 10.1038/s41398-021-01294-x
Trubetskoy V, Pardinas AF, Qi T, Panagiotaropoulou G, Awasthi S, Bigdeli TB, et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature. 2022;604:502–8.
pubmed: 35396580
pmcid: 9392466
doi: 10.1038/s41586-022-04434-5
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–72.
pubmed: 18035408
doi: 10.1016/j.cell.2007.11.019
Brennand KJ, Simone A, Jou J, Gelboin-Burkhart C, Tran N, Sangar S, et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature. 2011;473:221–5.
pubmed: 21490598
pmcid: 3392969
doi: 10.1038/nature09915
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.
pubmed: 28242870
doi: 10.1038/mp.2016.260
Vadodaria KC, Ji Y, Skime M, Paquola A, Nelson T, Hall-Flavin D, et al. Serotonin-induced hyperactivity in SSRI- resistant major depressive disorder patient-derived neurons. Mol Psychiatry. 2019;24:795–807.
pubmed: 30700803
doi: 10.1038/s41380-019-0363-y
Mertens J, Herdy JR, Traxler L, Schafer ST, Schlachetzki JCM, Bohnke L, et al. Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients. Cell Stem Cell. 2021;28:1533–48. e6.
pubmed: 33910058
pmcid: 8423435
doi: 10.1016/j.stem.2021.04.004
Hussein Y, Tripathi U, Choudhary A, Nayak R, Peles D, Rosh I, et al. Early maturation and hyperexcitability is a shared phenotype of cortical neurons derived from different ASD-associated mutations. Transl Psychiatry. 2023;13:246.
pubmed: 37414777
pmcid: 10326262
doi: 10.1038/s41398-023-02535-x
Stern S, Lau S, Manole A, Rosh I, Percia MM, Ben Ezer R, et al. Reduced synaptic activity and dysregulated extracellular matrix pathways in midbrain neurons from Parkinson’s disease patients. NPJ Parkinson’s disease. 2022;8:103.
pubmed: 35948563
pmcid: 9365794
doi: 10.1038/s41531-022-00366-z
Sarkar A, Mei A, Paquola ACM, Stern S, Bardy C, Klug JR, et al. Efficient generation of CA3 neurons from human pluripotent stem cells enables modeling of hippocampal connectivity in vitro. Cell Stem Cell. 2018;22:684–97. e9.
pubmed: 29727680
pmcid: 6345574
doi: 10.1016/j.stem.2018.04.009
Chiang CH, Su Y, Wen Z, Yoritomo N, Ross CA, Margolis RL, et al. Integration-free induced pluripotent stem cells derived from schizophrenia patients with a DISC1 mutation. Mol Psychiatry. 2011;16:358–60.
pubmed: 21339753
pmcid: 4005725
doi: 10.1038/mp.2011.13
Pedrosa E, Sandler V, Shah A, Carroll R, Chang C, Rockowitz S, et al. Development of patient-specific neurons in schizophrenia using induced pluripotent stem cells. J Neurogenet. 2011;25:88–103.
pubmed: 21797804
doi: 10.3109/01677063.2011.597908
Uzuneser TC, Speidel J, Kogias G, Wang AL, de Souza Silva MA, Huston JP, et al. Disrupted-in-schizophrenia 1 (DISC1) overexpression and juvenile immune activation cause sex-specific schizophrenia-related psychopathology in rats. Front Psychiatry. 2019;10:222.
pubmed: 31057438
pmcid: 6465888
doi: 10.3389/fpsyt.2019.00222
Page SC, Sripathy SR, Farinelli F, Ye Z, Wang Y, Hiler DJ, et al. Electrophysiological measures from human iPSC- derived neurons are associated with schizophrenia clinical status and predict individual cognitive performance. Proc Natl Acad Sci USA. 2022;119:e2109395119.
pubmed: 35017298
pmcid: 8784142
doi: 10.1073/pnas.2109395119
Tavitian A, Song W, Schipper HM. Dentate gyrus immaturity in schizophrenia. Neuroscientist. 2019;25:528–47.
pubmed: 30674225
doi: 10.1177/1073858418824072
Bohlken MM, Brouwer RM, Mandl RC, Van den Heuvel MP, Hedman AM, De Hert M, et al. Structural brain connectivity as a genetic marker for schizophrenia. JAMA Psychiatry. 2016;73:11–9.
pubmed: 26606729
doi: 10.1001/jamapsychiatry.2015.1925
Brant B, Stern T, Shekhidem HA, Mizrahi L, Rosh I, Stern Y, et al. IQSEC2 mutation associated with epilepsy, intellectual disability, and autism results in hyperexcitability of patient-derived neurons and deficient synaptic transmission. Mol Psychiatry. 2021;26:7498–508.
pubmed: 34535765
pmcid: 8873005
doi: 10.1038/s41380-021-01281-0
Yuan SH, Martin J, Elia J, Flippin J, Paramban RI, Hefferan MP, et al. Cell-surface marker signatures for the isolation of neural stem cells, glia and neurons derived from human pluripotent stem cells. PLoS ONE. 2011;6:e17540.
pubmed: 21407814
pmcid: 3047583
doi: 10.1371/journal.pone.0017540
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.
pubmed: 23104886
doi: 10.1093/bioinformatics/bts635
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.
pubmed: 25516281
pmcid: 4302049
doi: 10.1186/s13059-014-0550-8
Jaffe AE, Hoeppner DJ, Saito T, Blanpain L, Ukaigwe J, Burke EE, et al. Profiling gene expression in the human dentate gyrus granule cell layer reveals insights into schizophrenia and its genetic risk. Nat Neurosci. 2020;23:510–9.
pubmed: 32203495
doi: 10.1038/s41593-020-0604-z
Santos R, Linker SB, Stern S, Mendes APD, Shokhirev MN, Erikson G, et al. Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients. Mol Psychiatry. 2021;26:2440–56.
pubmed: 33398088
pmcid: 9129103
doi: 10.1038/s41380-020-00981-3
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.
pubmed: 29507296
pmcid: 5838215
doi: 10.1038/s41398-018-0102-1
Okerlund ND, Cheyette BN. Synaptic Wnt signaling-a contributor to major psychiatric disorders? J Neurodev Disord. 2011;3:162–74.
pubmed: 21533542
pmcid: 3180925
doi: 10.1007/s11689-011-9083-6
Hussaini SM, Choi CI, Cho CH, Kim HJ, Jun H, Jang MH. Wnt signaling in neuropsychiatric disorders: ties with adult hippocampal neurogenesis and behavior. Neurosci Biobehav Rev. 2014;47:369–83.
pubmed: 25263701
doi: 10.1016/j.neubiorev.2014.09.005
Wei Z, Wang L, Xuan J, Che R, Du J, Qin S, et al. Association analysis of serotonin receptor 7 gene (HTR7) and risperidone response in Chinese schizophrenia patients. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:547–51.
pubmed: 19233240
doi: 10.1016/j.pnpbp.2009.02.008
Ikeda M, Iwata N, Kitajima T, Suzuki T, Yamanouchi Y, Kinoshita Y, et al. Positive association of the serotonin 5-HT7 receptor gene with schizophrenia in a Japanese population. Neuropsychopharmacology. 2006;31:866–71.
pubmed: 16192982
doi: 10.1038/sj.npp.1300901
Han EB, Stevens CF. Development regulates a switch between post- and presynaptic strengthening in response to activity deprivation. Proc Natl Acad Sci USA. 2009;106:10817–22.
pubmed: 19509338
pmcid: 2705571
doi: 10.1073/pnas.0903603106
Stern S, Segal M, Moses E. Involvement of potassium and cation channels in hippocampal abnormalities of embryonic Ts65Dn and Tc1 trisomic mice. EBioMedicine. 2015;2:1048–62.
pubmed: 26501103
pmcid: 4588457
doi: 10.1016/j.ebiom.2015.07.038
Obi-Nagata K, Temma Y, Hayashi-Takagi A. Synaptic functions and their disruption in schizophrenia: From clinical evidence to synaptic optogenetics in an animal model. Proc Jpn Acad Ser B Phys Biol Sci. 2019;95:179–97.
pubmed: 31080187
pmcid: 6742729
doi: 10.2183/pjab.95.014
Berdenis van Berlekom A, Muflihah CH, Snijders G, MacGillavry HD, Middeldorp J, Hol EM, et al. Synapse pathology in schizophrenia: a meta-analysis of postsynaptic elements in postmortem brain studies. Schizophr Bull. 2020;46:374–86.
pubmed: 31192350
Osimo EF, Beck K, Reis Marques T, Howes OD. Synaptic loss in schizophrenia: a meta-analysis and systematic review of synaptic protein and mRNA measures. Mol Psychiatry. 2019;24:549–61.
pubmed: 29511299
doi: 10.1038/s41380-018-0041-5
Sellgren CM, Gracias J, Watmuff B, Biag JD, Thanos JM, Whittredge PB, et al. Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning. Nat Neurosci. 2019;22:374–85.
pubmed: 30718903
pmcid: 6410571
doi: 10.1038/s41593-018-0334-7
Bipolar D, Schizophrenia Working Group of the Psychiatric Genomics Consortium. Electronic address drve, Bipolar D, Schizophrenia Working Group of the Psychiatric Genomics C. Genomic dissection of bipolar disorder and schizophrenia, including 28 subphenotypes. Cell. 2018;173:1705–15. e16.
doi: 10.1016/j.cell.2018.05.046
Bigdeli TB, Fanous AH, Li Y, Rajeevan N, Sayward F, Genovese G, et al. Genome-wide association studies of schizophrenia and bipolar disorder in a diverse cohort of US veterans. Schizophr Bull. 2021;47:517–29.
pubmed: 33169155
doi: 10.1093/schbul/sbaa133
Lichtenstein P, Yip BH, Bjork C, Pawitan Y, Cannon TD, Sullivan PF, et al. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet. 2009;373:234–9.
pubmed: 19150704
doi: 10.1016/S0140-6736(09)60072-6
Stern S, Sarkar A, Galor D, Stern T, Mei A, Stern Y, et al. A physiological instability displayed in hippocampal neurons derived from lithium-nonresponsive bipolar disorder patients. Biol Psychiatry. 2020;88:150–8.
pubmed: 32278494
pmcid: 10871148
doi: 10.1016/j.biopsych.2020.01.020
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;88:139–49.
pubmed: 31732108
doi: 10.1016/j.biopsych.2019.09.018
Douaud G, Mackay C, Andersson J, James S, Quested D, Ray MK, et al. Schizophrenia delays and alters maturation of the brain in adolescence. Brain. 2009;132:2437–48.
pubmed: 19477963
doi: 10.1093/brain/awp126
Cannon M, Caspi A, Moffitt TE, Harrington H, Taylor A, Murray RM, et al. Evidence for early-childhood, pan- developmental impairment specific to schizophreniform disorder: results from a longitudinal birth cohort. Arch Gen Psychiatry. 2002;59:449–56.
pubmed: 11982449
doi: 10.1001/archpsyc.59.5.449
Brouwer RM, Klein M, Grasby KL, Schnack HG, Jahanshad N, Teeuw J, et al. Genetic variants associated with longitudinal changes in brain structure across the lifespan. Nat Neurosci. 2022;25:421–32.
pubmed: 35383335
pmcid: 10040206
doi: 10.1038/s41593-022-01042-4
Vivar C, van Praag H. Functional circuits of new neurons in the dentate gyrus. Front Neural Circuits. 2013;7:15.
pubmed: 23443839
pmcid: 3580993
doi: 10.3389/fncir.2013.00015
Tashiro A, Sandler VM, Toni N, Zhao C, Gage FH. NMDA-receptor-mediated, cell-specific integration of new neurons in adult dentate gyrus. Nature. 2006;442:929–33.
pubmed: 16906136
doi: 10.1038/nature05028
Rasanen N, Tiihonen J, Koskuvi M, Lehtonen S, Koistinaho J. The iPSC perspective on schizophrenia. Trends Neurosci. 2022;45:8–26.
pubmed: 34876311
doi: 10.1016/j.tins.2021.11.002
Rosoklija G, Toomayan G, Ellis SP, Keilp J, Mann JJ, Latov N, et al. Structural abnormalities of subicular dendrites in subjects with schizophrenia and mood disorders: preliminary findings. Arch Gen Psychiatry. 2000;57:349–56.
pubmed: 10768696
doi: 10.1001/archpsyc.57.4.349
Larsen NY, Vihrs N, Moller J, Sporring J, Tan X, Li X, et al. Layer III pyramidal cells in the prefrontal cortex reveal morphological changes in subjects with depression, schizophrenia, and suicide. Transl Psychiatry. 2022;12:363.
pubmed: 36064829
pmcid: 9445178
doi: 10.1038/s41398-022-02128-0