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Molecular psychiatry
Feb 07, 2025;

��IV spectrin abundancy, cellular distribution and sensitivity to AKT/GSK3 regulation in schizophrenia.

Jessica Di Re, Michela Marini, Syed Ibrar Hussain, Aditya K Singh, Akshaya Venkatesh, Musaad A Alshammari, Tahani K Alshammari, Abdul-Rizaq Ali Hamoud, Ali Sajid Imami, Zahra Haghighijoo, Nickolas Fularcyzk, Laura Stertz, Derek Hawes, Angela Mosebarger, Jordan Jernigan, Claire Chaljub, Ralda Nehme, Consuelo Walss-Bass, Anton Schulmann, Marquis P Vawter, Robert McCullumsmith, Robert D Damoiseaux, Agenor Limon, Demetrio Labate, Michael F Wells, Fernanda Laezza
Author Information
  1. Jessica Di Re: Department of Pharmacology & Toxicology, University of Texas Medical Branch at Galveston, Galveston, TX, USA.
  2. Michela Marini: Department of Mathematics, University of Houston, Houston, TX, USA. ORCID
  3. Syed Ibrar Hussain: Department of Mathematics, University of Houston, Houston, TX, USA.
  4. Aditya K Singh: Department of Pharmacology & Toxicology, University of Texas Medical Branch at Galveston, Galveston, TX, USA. ORCID
  5. Akshaya Venkatesh: MD-PhD Combined Program, University of Texas Medical Branch at Galveston, Galveston, TX, USA.
  6. Musaad A Alshammari: Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia.
  7. Tahani K Alshammari: Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia.
  8. Abdul-Rizaq Ali Hamoud: Department of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA.
  9. Ali Sajid Imami: Department of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA. ORCID
  10. Zahra Haghighijoo: Department of Pharmacology & Toxicology, University of Texas Medical Branch at Galveston, Galveston, TX, USA.
  11. Nickolas Fularcyzk: Department of Mathematics, University of Houston, Houston, TX, USA.
  12. Laura Stertz: Louis A. Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA. ORCID
  13. Derek Hawes: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  14. Angela Mosebarger: Department of Pharmacology & Toxicology, University of Texas Medical Branch at Galveston, Galveston, TX, USA.
  15. Jordan Jernigan: Department of Pharmacology & Toxicology, University of Texas Medical Branch at Galveston, Galveston, TX, USA.
  16. Claire Chaljub: Department of Pharmacology & Toxicology, University of Texas Medical Branch at Galveston, Galveston, TX, USA.
  17. Ralda Nehme: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. ORCID
  18. Consuelo Walss-Bass: Louis A. Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA.
  19. Anton Schulmann: Department of Psychiatry, Columbia University Irving Medical Center, New York State Psychiatric Institute, New York, NY, USA.
  20. Marquis P Vawter: Functional Genomics Laboratory, Department of Psychiatry & Human Behavior, University of California, Irvine, Irvine, CA, USA.
  21. Robert McCullumsmith: Department of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA. ORCID
  22. Robert D Damoiseaux: Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA.
  23. Agenor Limon: Department of Neurology, University of Texas Medical Branch at Galveston, Galveston, TX, USA. ORCID
  24. Demetrio Labate: Department of Mathematics, University of Houston, Houston, TX, USA.
  25. Michael F Wells: Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
  26. Fernanda Laezza: Department of Pharmacology & Toxicology, University of Texas Medical Branch at Galveston, Galveston, TX, USA. felaezza@utmb.edu. ORCID
PMID: 39920295 DOI: 10.1038/s41380-025-02917-1

Abstract

Schizophrenia (SCZ) is a complex psychiatric disorder with unclear biological mechanisms. Spectrins, cytoskeletal proteins linked to neurodevelopmental disorders, are regulated by the AKT/GSK3 pathway, which is implicated in SCZ. However, the impact of SCZ-related dysregulation of this pathway on spectrin expression and distribution remains unexplored. Here, we show that ��IV spectrin protein levels were reduced in neurons of the dorsolateral prefrontal cortex in SCZ postmortem samples compared to healthy control (HC) from the Human Brain Collection Core (HBCC). To investigate potential links between ��IV spectrin and the AKT/GSK3 pathway, we analyzed the PsychEncode dataset, revealing elevated SPTBN4 and AKT2 mRNA levels with correlated gene transcription in both HCs and individuals with SCZ. Next, computational tools were employed to identify potential AKT and GSK3 phosphorylation sites on ��IV spectrin, and two GSK3 sites were validated through in vitro assays. To assess whether ��IV spectrin distribution and sensitivity to AKT/GSK3 are altered in SCZ, we used iPSC-derived neurons from two independent cohorts of patients with significantly increased familial genetic risk for the disorder. Alteration in ��IV spectrin levels and sensitivity to AKT/GSK3 inhibitors were consistently observed across both cohorts. Importantly, a Random Forest classifier applied to ��IV spectrin imaging achieved up to 98% accuracy in classifying cells by diagnosis in postmortem samples, and by diagnosis or diagnosis �� perturbation in iPSC samples. These findings reveal altered ��IV spectrin levels and AKT/GSK3 sensitivity in SCZ, identifying ��IV spectrin image-based endophenotypes as robust, generalizable predictive biomarkers of SCZ, with the potential for scalable clinical applications.

References

  1. McGrath J, Saha S, Chant D, Welham J. Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol Rev. 2008;30:67���76. [PMID: 18480098]
  2. Gaebel W, Kerst A, Stricker J. Classification and diagnosis of schizophrenia or other primary psychotic disorders: Changes from icd-10 to icd-11 and implementation in clinical practice. Psychiatr Danub. 2021;32:320���4. [DOI: 10.24869/psyd.2020.320]
  3. Singh T, Poterba T, Curtis D, Akil H, Al Eissa M, Barchas JD, et al. Rare coding variants in ten genes confer substantial risk for schizophrenia. Nature. 2022;604:509���16. [PMID: 35396579]
  4. Trubetskoy V, Pardi��as 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. [PMID: 35396580]
  5. Fromer M, Roussos P, Sieberts SK, Johnson JS, Kavanagh DH, Perumal TM, et al. Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat Neurosci. 2016;19:1442���53. [PMID: 27668389]
  6. Gandal MJ, Zhang P, Hadjimichael E, Walker RL, Chen C, Liu S, et al. Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science. 2018;362:1���15. [DOI: 10.1126/science.aat8127]
  7. Akula N, Marenco S, Johnson K, Feng N, Zhu K, Schulmann A, et al. Deep transcriptome sequencing of subgenual anterior cingulate cortex reveals cross-diagnostic and diagnosis-specific RNA expression changes in major psychiatric disorders. Neuropsychopharmacology. 2021;46:1364���72. [PMID: 33558674]
  8. Ripke S, Neale BM, Corvin A, Walters JTR, Farh KH, Holmans PA, et al. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421���7. [>PMCID: ]
  9. Purcell SM, Moran JL, Fromer M, Ruderfer D, Solovieff N, Roussos P, et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature. 2014;506:185���90. [PMID: 24463508]
  10. Avramopoulos D. Recent advances in the genetics of schizophrenia. Mol Neuropsychiatry. 2018;4:35���51. [PMID: 29998117]
  11. Schmitt A, Leonardi-Essmann F, Durrenberger PF, Wichert SP, Spanagel R, Arzberger T, et al. Structural synaptic elements are differentially regulated in superior temporal cortex of schizophrenia patients. Eur Arch Psychiatry Clin Neurosci. 2012;262:565���77. [PMID: 22441714]
  12. Xia Y, Xia C, Jiang Y, Chen Y, Zhou J, Dai R, et al. Transcriptomic sex differences in postmortem brain samples from patients with psychiatric disorders. Sci Transl Med. 2024;16:eadh9974. [PMID: 38781321]
  13. Dubey S, Bhembre N, Bodas S, Veer S, Ghose A, Callan-Jones A, et al. The axonal actin-spectrin lattice acts as a tension buffering shock absorber. Elife. 2020;9:1���22. [DOI: 10.7554/eLife.51772]
  14. Lorenzo DN. Cargo hold and delivery: ankyrins, spectrins, and their functional patterning of neurons. Cytoskeleton (Hoboken). 2020;77:129���48. [PMID: 32034889]
  15. Davis JQ, Bennett V. Ankyrin-binding activity of nervous system cell adhesion molecules expressed in adult brain. J Cell Sci. 1993;1993:109���17. [DOI: 10.1242/jcs.1993.Supplement_17.16]
  16. Jones SL, Svitkina TM. Axon initial segment cytoskeleton: architecture, development, and role in neuron polarity. Neural Plast. 2016;2016:6808293. [PMID: 27493806]
  17. Nelson AD, Jenkins PM. Axonal membranes and their domains: assembly and function of the axon initial segment and node of Ranvier. Front Cell Neurosci. 2017;11:1���17. [DOI: 10.3389/fncel.2017.00136]
  18. Machnicka B, Czogalla A, Hryniewicz-Jankowska A, Bogus��awska DM, Grochowalska R, Heger E, et al. Spectrins: a structural platform for stabilization and activation of membrane channels, receptors and transporters. Biochim Biophys Acta - Biomembr. 2014;1838:620���34. [DOI: 10.1016/j.bbamem.2013.05.002]
  19. Kuba H, Oichi Y, Ohmori H. Presynaptic activity regulates Na(+) channel distribution at the axon initial segment. Nature. 2010;465:1075���8. [PMID: 20543825]
  20. Grubb MS, Burrone J. Activity-dependent relocation of the axon initial segment fine-tunes neuronal excitability. Nature. 2010;465:1070���4. [PMID: 20543823]
  21. Ogawa Y, Rasband MN. The functional organization and assembly of the axon initial segment. Curr Opin Neurobiol. 2008;18:307���13. [PMID: 18801432]
  22. Hund TJ, Koval OM, Li J, Wright PJ, Qian L, Snyder JS, et al. A ��IV-spectrin/CaMKII signaling complex is essential for membrane excitability in mice. J Clin Invest. 2010;120:3508���19. [PMID: 20877009]
  23. Szu-Yu Ho T, Rasband MN. Maintenance of neuronal polarity. Dev Neurobiol. 2011;71:474���82. [PMID: 21557501]
  24. Evans MD, Dumitrescu AS, Kruijssen DLH, Taylor SE, Grubb MS. Rapid modulation of axon initial segment length influences repetitive spike firing. Cell Rep. 2015;13:1233���45. [PMID: 26526995]
  25. Nip K, Kashiwagura S, Kim JH. Loss of ��4-spectrin impairs Nav channel clustering at the heminode and temporal fidelity of presynaptic spikes in developing auditory brain. Sci Rep. 2022;12:5854. [PMID: 35393465]
  26. Lorenzo DN, Edwards RJ, Slavutsky AL. Spectrins: molecular organizers and targets of neurological disorders. Nat Rev Neurosci. 2023;24:195���212. [PMID: 36697767]
  27. Di Re J, Hsu W-CJ, Kayasandik CB, Fularczyk N, James TF, Nenov MN, et al. Inhibition of AKT signaling alters ��IV spectrin distribution at the AIS and increases neuronal excitability. Front Mol Neurosci. 2021;14:643860. [PMID: 34276302]
  28. Marosi M, Nenov MN, Di Re J, Dvorak NM, Alshammari M, Laezza F. Inhibition of the Akt/PKB kinase increases Nav1.6-mediated currents and neuronal excitability in CA1 hippocampal pyramidal neurons. Int J Mol Sci. 2022;23:1700. [PMID: 35163623]
  29. Frame S, Cohen P, Biondi RM. A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Mol Cell. 2001;7:1321���7. [PMID: 11430833]
  30. Emamian ES. AKT/GSK3 signaling pathway and schizophrenia. Front Mol Neurosci. 2012;5:33. [PMID: 22435049]
  31. McGuire JL, Depasquale EA, Funk AJ, O���Donnovan SM, Hasselfeld K, Marwaha S, et al. Abnormalities of signal transduction networks in chronic schizophrenia. npj Schizophr. 2017;3:30. [PMID: 28900113]
  32. Chadha R, Alganem K, Mccullumsmith RE, Meador-Woodruff JH. mTOR kinase activity disrupts a phosphorylation signaling network in schizophrenia brain. Mol Psychiatry. 2021;26:6868���79. [PMID: 33990769]
  33. Li S, Lu C, Kang L, Li Q, Chen H, Zhang H, et al. Study on correlations of BDNF, PI3K, AKT and CREB levels with depressive emotion and impulsive behaviors in drug-na��ve patients with first-episode schizophrenia. BMC Psychiatry. 2023;23:1���11.
  34. Stertz L, Di Re J, Pei G, Fries GR, Mendez E, Li S, et al. Convergent genomic and pharmacological evidence of PI3K/GSK3 signaling alterations in neurons from schizophrenia patients. Neuropsychopharmacology. 2021;46:673���82. [PMID: 33288841]
  35. Mizuki Y, Sakamoto S, Okahisa Y, Yada Y, Hashimoto N, Takaki M, et al. Mechanisms underlying the comorbidity of schizophrenia and type 2 diabetes mellitus. Int J Neuropsychopharmacol. 2021;24:367���82. [PMID: 33315097]
  36. Johnson JL, Yaron TM, Huntsman EM, Kerelsky A, Song J, Regev A, et al. An atlas of substrate specificities for the human serine/threonine kinome. Nature. 2023;613:759���66. [PMID: 36631611]
  37. Walss-Bass C, Liu W, Lew DF, Villegas R, Montero P, Dassori A, et al. A novel missense mutation in the transmembrane domain of neuregulin 1 is associated with schizophrenia. Biol Psychiatry. 2006;60:548���53. [PMID: 16730337]
  38. Fularczyk N, Di Re J, Stertz L, Walss-Bass C, Laezza F, Labate D. A learning based framework for disease prediction from images of human-derived pluripotent stem cells of schizophrenia patients. Neuroinformatics. 2022;20:513���23. [PMID: 35064871]
  39. Guss EJ, Sathe L, Dai A, Derebenskiy T, Vega AR, Eggan K, et al. Protocol for neurogenin-2-mediated induction of human stem cell-derived neural progenitor cells. STAR Protoc. 2024;5:102878. [PMID: 38335091]
  40. Nehme R, Zuccaro E, Ghosh SD, Li C, Sherwood JL, Pietilainen O, et al. Combining NGN2 programming with developmental patterning generates human excitatory neurons with NMDAR-mediated synaptic transmission. Cell Rep. 2018;23:2509���23. [PMID: 29791859]
  41. Di Re J, Kayasandik C, Botello���Lins G, Labate D, Laezza F. Imaging of the axon initial segment. Curr Protoc Neurosci. 2019;89:e78. [PMID: 31532918]
  42. Alshammari MA, Alshammari TK, Laezza F. Improved methods for fluorescence microscopy detection of macromolecules at the axon initial segment. Front Cell Neurosci. 2016;10:5. [PMID: 26909021]
  43. Bosch MK, Carrasquillo Y, Ransdell JL, Kanakamedala A, Ornitz DM, Nerbonne JM. Intracellular FGF14 (iFGF14) is required for spontaneous and evoked firing in cerebellar Purkinje neurons and for motor coordination and balance. J Neurosci. 2015;35:6752���69. [PMID: 25926453]
  44. Van Griethuysen JJM, Fedorov A, Parmar C, Hosny A, Aucoin N, Narayan V, et al. Computational radiomics system to decode the radiographic phenotype. Cancer Res. 2017;77:e104���7. [PMID: 29092951]
  45. Haralick RM, Dinstein I, Shanmugam K. Textural features for image classification. IEEE Trans Syst Man Cybern. 1973;SMC-3:610���21. [DOI: 10.1109/TSMC.1973.4309314]
  46. Law CW, Chen Y, Shi W, Smyth GK. Voom: precision weights unlock linear model analysis tools for RNA-seq read counts. Genome Biol. 2014;15:1���17. [DOI: 10.1186/gb-2014-15-2-r29]
  47. Leek JT, Johnson WE, Parker HS, Jaffe AE, Storey JD. The SVA package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics. 2012;28:882���3. [PMID: 22257669]
  48. Kumar M, Michael S, Alvarado-Valverde J, M��sz��ros B, S��mano-S��nchez H, Zeke A, et al. The Eukaryotic Linear Motif resource: 2022 release. Nucleic Acids Res. 2022;50:D497���508. [PMID: 34718738]
  49. Bzdok D, Altman N, Krzywinski M. Points of Significance: Statistics versus machine learning. Nat Methods. 2018;15:233���4. [PMID: 30100822]
  50. Alganem K, Hamoud AR, Creeden JF, Henkel ND, Imami AS, Joyce AW, et al. The active kinome: the modern view of how active protein kinase networks fit in biological research. Curr Opin Pharmacol. 2022;62:117���29. [PMID: 34968947]
  51. Sahay S, Hamoud A-R, Osman M, Pulvender P, McCullumsmith RE. Expression of WNT signaling genes in the dorsolateral prefrontal cortex in schizophrenia. Brain Sci. 2024;14:649. [PMID: 39061390]
  52. Glahn DC, Nimgaonkar VL, Ravent��s H, Contreras J, McIntosh AM, Thomson PA, et al. Rediscovering the value of families for psychiatric genetics research. Mol Psychiatry. 2019;24:523���35. [PMID: 29955165]
  53. Uhrhammer N, Lange E, Porras O, Naeim A, Chen X, Sheikhavandi S, et al. Sublocalization of an ataxia-telangiectasia gene distal to D11S384 by ancestral haplotyping in Costa Rican families. Am J Hum Genet. 1995;57:103���11. [PMID: 7611278]
  54. Walss-Bass C, Escamilla MA, Raventos H, Montero AP, Armas R, Dassori A, et al. Evidence of genetic overlap of schizophrenia and bipolar disorder: linkage disequilibrium analysis of chromosome 18 in the Costa Rican population. Am J Med Genet - Neuropsychiatr Genet. 2005;139 B:54���60. [DOI: 10.1002/ajmg.b.30207]
  55. Walss-Bass C, Raventos H, Montero AP, Armas R, Dassori A, Contreras S, et al. Association analyses of the neuregulin 1 gene with schizophrenia and manic psychosis in a Hispanic population. Acta Psychiatr Scand. 2006;113:314���21. [PMID: 16638076]
  56. Walss-Bass C, Soto-Bernardini MC, Johnson-Pais T, Leach RJ, Ontiveros A, Nicolini H, et al. Methionine sulfoxide reductase: a novel schizophrenia candidate gene. Am J Med Genet Part B Neuropsychiatr Genet. 2009;150:219���25. [DOI: 10.1002/ajmg.b.30791]
  57. Chavarr��a-Siles I, Contreras-Rojas J, Hare E, Walss-Bass C, Quezada P, Dassori A, et al. Cannabinoid receptor 1 gene (CNR1) and susceptibility to a quantitative phenotype for hebephrenic schizophrenia. Am J Med Genet Part B Neuropsychiatr Genet. 2008;147:279���84. [DOI: 10.1002/ajmg.b.30592]
  58. Chavarr��a-Siles I, Walss-Bass C, Quezada P, Dassori A, Contreras S, Medina R, et al. TGFB-induced factor (TGIF): a candidate gene for psychosis on chromosome 18p. Mol Psychiatry. 2007;12:1033���41. [PMID: 17440433]
  59. Contreras J, Hernndez S, Quezada P, Dassori A, Walss-Bass C, Escamilla M, et al. Association of serotonin transporter promoter gene polymorphism (5-HTTLPR) with depression in Costa Rican schizophrenic patients. J Neurogenet. 2010;24:83���9. [PMID: 20397838]
  60. Dae Lee B, Walss-Bass C, Thompson PM, Dassori A, Montero PA, Medina R, et al. Malic enzyme 2 and susceptibility to psychosis and mania. Psychiatry Res. 2007;150:1���11. [DOI: 10.1016/j.psychres.2006.06.001]
  61. Tahirovic S, Bradke F. Neuronal polarity. Cold Spring Harb Perspect Biol. 2009;1:a001644. [PMID: 20066106]
  62. Loe-Mie Y, Plan��on C, Dubertret C, Yoshikawa T, Yalcin B, Collins SC, et al. De novo variants found in three distinct schizophrenia populations hit a common core gene network related to microtubule and actin cytoskeleton gene ontology classes. Life (Basel, Switzerland). 2024;14:244. [PMID: 38398753]
  63. McCarthy SE, Makarov V, Kirov G, Addington AM, McClellan J, Yoon S, et al. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet. 2009;41:1223���7. [PMID: 19855392]
  64. Blizinsky KD, Diaz-Castro B, Forrest MP, Sch��rmann B, Bach AP, Martin-de-Saavedra MD, et al. Reversal of dendritic phenotypes in 16p11.2 microduplication mouse model neurons by pharmacological targeting of a network hub. Proc Natl Acad Sci USA. 2016;113:8520���5. [PMID: 27402753]
  65. Hetman M, Hsuan SL, Habas A, Higgins MJ, Xia Z. ERK1/2 antagonizes glycogen synthase kinase-3beta-induced apoptosis in cortical neurons. J Biol Chem. 2002;277:49577���84. [PMID: 12393899]
  66. Cousin MA, Creighton BA, Breau KA, Spillmann RC, Torti E, Dontu S, et al. Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome. Nat Genet. 2021;53:1006���21. [PMID: 34211179]
  67. Wang C-C, Ortiz-Gonz��lez XR, Yum SW, Gill SM, White A, Kelter E, et al. ��IV spectrinopathies cause profound intellectual disability, congenital hypotonia, and motor axonal neuropathy. Am J Hum Genet. 2018;102:1158���68. [PMID: 29861105]
  68. Writzl K, Primec ZR, Stra��i��ar BG, Osredkar D, Pe��ari��-Megli�� N, Kranjc BS, et al. Early onset West syndrome with severe hypomyelination and coloboma-like optic discs in a girl with SPTAN1 mutation. Epilepsia. 2012;53:106���10. [DOI: 10.1111/j.1528-1167.2012.03437.x]
  69. Tohyama J, Nakashima M, Nabatame S, Gaik-Siew C, Miyata R, Rener-Primec Z, et al. SPTAN1 encephalopathy: distinct phenotypes and genotypes. J Hum Genet. 2015;60:167���73. [PMID: 25631096]
  70. Tuncay IO, Parmalee NL, Khalil R, Kaur K, Kumar A, Jimale M, et al. Analysis of recent shared ancestry in a familial cohort identifies coding and noncoding autism spectrum disorder variants. NPJ Genomic Med. 2022;7:13. [DOI: 10.1038/s41525-022-00284-2]
  71. Buelow M, S����muth D, Smith LD, Aryani O, Castiglioni C, Stenzel W, et al. Novel bi-allelic variants expand the SPTBN4-related genetic and phenotypic spectrum. Eur J Hum Genet. 2021;29:1121���8. [PMID: 33772159]
  72. Hoffman GE, Bendl J, Voloudakis G, Montgomery KS, Sloofman L, Wang YC, et al. CommonMind Consortium provides transcriptomic and epigenomic data for schizophrenia and bipolar disorder. Sci Data. 2019;6:1���14. [DOI: 10.1038/s41597-019-0183-6]
  73. Jiang S, Huang H, Zhou J, Li H, Duan M, Yao D, et al. Progressive trajectories of schizophrenia across symptoms, genes, and the brain. BMC Med. 2023;21:1���16. [DOI: 10.1186/s12916-023-02935-2]
  74. Buccitelli C, Selbach M. mRNAs, proteins and the emerging principles of gene expression control. Nat Rev Genet. 2020;21:630���44. [PMID: 32709985]
  75. Cruz DA, Weaver C, Lovallo EM, Melchitzky DS, Lewis DA. Selective alterations in postsynaptic markers of chandelier cell inputs to cortical pyramidal neurons in subjects with schizophrenia HHS public access. Neuropsychopharmacology. 2009;34:2112���24. [PMID: 19322171]
  76. Jamann N, Dannehl D, Lehmann N, Wagener R, Thielemann C, Schultz C, et al. Sensory input drives rapid homeostatic scaling of the axon initial segment in mouse barrel cortex. Nat Commun. 2021;12:1���14. [DOI: 10.1038/s41467-020-20232-x]
  77. Grubb MS, Shu Y, Kuba H, Rasband MN, Wimmer VC, Bender KJ. Short- and long-term plasticity at the axon initial segment. J Neurosci. 2011;31:16049���55. [PMID: 22072655]
  78. Yamada R, Kuba H. Structural and functional plasticity at the axon initial segment. Front Cell Neurosci. 2016;10:250. [PMID: 27826229]
  79. 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;119:1���12. [DOI: 10.1073/pnas.2109395119]
  80. Yoshihara S, Jiang X, Morikawa M, Ogawa T, Ichinose S, Yabe H, et al. Betaine ameliorates schizophrenic traits by functionally compensating for KIF3-based CRMP2 transport. Cell Rep. 2021;35:108971. [PMID: 33852848]
  81. McGuire JL, Hammond JH, Yates SD, Chen D, Haroutunian V, Meador-Woodruff JH, et al. Altered serine/threonine kinase activity in schizophrenia. Brain Res. 2014;1568:42���54. [PMID: 24780530]
  82. Kozlovsky N, Regenold WT, Levine J, Rapoport A, Belmaker RH, Agam G. GSK-3beta in cerebrospinal fluid of schizophrenia patients. J Neural Transm. 2004;111:1093���8. [PMID: 15254796]
  83. Lovestone S, Killick R, Di Forti M, Murray R. Schizophrenia as a GSK-3 dysregulation disorder. Trends Neurosci. 2007;30:142���9. [PMID: 17324475]
  84. Devine EA, Imami AS, Eby H, Sahay S, Hamoud AR, Golchin H, et al. Neuronal alterations in AKT isotype expression in schizophrenia. Mol Psychiatry. 2024.
  85. Kozlovsky N, Belmaker RH, Agam G. Low GSK-3 activity in frontal cortex of schizophrenic patients. Schizophr Res. 2001;52:101���5. [PMID: 11595396]

Grants

  1. UT BRAIN/University of Texas System (UT)
  2. R01MH107487/U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)
  3. MH121102/U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)
  4. R01ES031823/U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS)
  5. R01AG070255/U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
  6. NIMH Intramural Research Program/U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)
  7. R01MH124351/U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)
  8. P30CA016042/U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
  9. MP-TSM-00002738/Simons Foundation
  10. K22 MH126015/NIMH NIH HHS
  11. R00MH119327/U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)
  12. Young Investigator Award/Brain and Behavior Research Foundation (Brain & Behavior Research Foundation)
  13. T32ES007254/U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS)
  14. R00 MH119327/NIMH NIH HHS
  15. R01 MH126522/U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)
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Created with Highcharts 10.0.0spectrin��IVSCZAKT/GSK3levelssensitivitypathwaydistributionsamplespotentialdiagnosisdisorderneuronspostmortemGSK3sitestwoalteredcohortsSchizophreniacomplexpsychiatricunclearbiologicalmechanismsSpectrinscytoskeletalproteinslinkedneurodevelopmentaldisordersregulatedimplicatedHoweverimpactSCZ-relateddysregulationexpressionremainsunexploredshowproteinreduceddorsolateralprefrontalcortexcomparedhealthycontrolHCHumanBrainCollectionCoreHBCCinvestigatelinksanalyzedPsychEncodedatasetrevealingelevatedSPTBN4AKT2mRNAcorrelatedgenetranscriptionHCsindividualsNextcomputationaltoolsemployedidentifyAKTphosphorylationvalidatedvitroassaysassesswhetherusediPSC-derivedindependentpatientssignificantlyincreasedfamilialgeneticriskAlterationinhibitorsconsistentlyobservedacrossImportantlyRandomForestclassifierappliedimagingachieved98%accuracyclassifyingcells��perturbationiPSCfindingsrevealidentifyingimage-basedendophenotypesrobustgeneralizablepredictivebiomarkersscalableclinicalapplicationsabundancycellularregulationschizophrenia

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