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In vivo study sheds new light on the dendritic spine pathology hypothesis of schizophrenia

Molecular Psychiatry volume 27, pages 1866–1868 (2022)Cite this article

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To date, the neuropathophysiology of schizophrenia has yet to be fully elucidated. Although structural brain abnormalities (including the reduced gray matter of some brain regions and hippocampus) have been frequently reported in schizophrenia [1,2,3], it is unclear whether these abnormalities represent intrinsic characteristics or are due to the effects of antipsychotics and illness progression. In addition, these abnormalities are typically subtle, lack regional specificity, and are difficult to replicate in most schizophrenia cases. Moreover, recent studies showed no evidence of genetic overlap between subcortical volume measurements and schizophrenia risk [4, 5], indicating that structural brain abnormalities may not be a typical neuropathological feature of schizophrenia.

In the process of describing the neuropathology of schizophrenia, reductions in dendritic spine density have been frequently reported [6,7,8,9,10,11,12]. Dendritic spines are small membranous protrusions located on the dendritic processes of neurons. As a major anatomical unit for memory storage and synaptic transmission, dendritic spines usually receive excitatory input from axons, and most excitatory synaptic transmission occurs in dendritic spines. Dendritic spine formation is a dynamic process, and the structural plasticity of dendritic spines plays pivotal roles in learning, memory, and other cognitive processes. In 2000, Glantz et al. reported decreased dendritic spine density of prefrontal cortical pyramidal neurons in schizophrenia [6]. Subsequently, decreased dendritic spine density in schizophrenia was repeatedly reported [7, 10, 13, 14]. These consistent neuropathological findings (i.e., decreased dendritic spine density in schizophrenia) support the dendritic spine pathology of schizophrenia [7,8,9, 15, 16].

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References

  1. Cahn W, Hulshoff Pol HE, Lems EB, van Haren NE, Schnack HG, van der Linden JA, et al. Brain volume changes in first-episode schizophrenia: a 1-year follow-up study. Arch Gen Psychiatry. 2002;59:1002–10.

    Article  Google Scholar 

  2. Steen RG, Mull C, McClure R, Hamer RM, Lieberman JA. Brain volume in first-episode schizophrenia: systematic review and meta-analysis of magnetic resonance imaging studies. Br J Psychiatry. 2006;188:510–8.

    Article  Google Scholar 

  3. Boos HB, Aleman A, Cahn W, Hulshoff Pol H, Kahn RS. Brain volumes in relatives of patients with schizophrenia: a meta-analysis. Arch Gen Psychiatry. 2007;64:297–304.

    Article  Google Scholar 

  4. Li M, Huang L, Wang J, Su B, Luo XJ. No association between schizophrenia susceptibility variants and macroscopic structural brain volume variation in healthy subjects. Am J Med Genet B Neuropsychiatr Genet. 2016;171B:160–8.

    Article  Google Scholar 

  5. Franke B, Stein JL, Ripke S, Anttila V, Hibar DP, van Hulzen KJE, et al. Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept. Nat Neurosci. 2016;19:420–31.

    Article  CAS  Google Scholar 

  6. Glantz LA, Lewis DA. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry. 2000;57:65–73.

    Article  CAS  Google Scholar 

  7. Konopaske GT, Lange N, Coyle JT, Benes FM. Prefrontal cortical dendritic spine pathology in schizophrenia and bipolar disorder. JAMA Psychiatry. 2014;71:1323–31.

    Article  Google Scholar 

  8. Penzes P, Cahill ME, Jones KA, VanLeeuwen JE, Woolfrey KM. Dendritic spine pathology in neuropsychiatric disorders. Nat Neurosci. 2011;14:285–93.

    Article  CAS  Google Scholar 

  9. Glausier JR, Lewis DA. Dendritic spine pathology in schizophrenia. Neuroscience. 2013;251:90–107.

    Article  CAS  Google Scholar 

  10. MacDonald ML, Alhassan J, Newman JT, Richard M, Gu H, Kelly RM, et al. Selective loss of smaller spines in schizophrenia. Am J Psychiatry. 2017;174:586–94.

    Article  Google Scholar 

  11. Hill JJ, Hashimoto T, Lewis DA. Molecular mechanisms contributing to dendritic spine alterations in the prefrontal cortex of subjects with schizophrenia. Mol Psychiatry. 2006;11:557–66.

    Article  CAS  Google Scholar 

  12. Moyer CE, Shelton MA, Sweet RA. Dendritic spine alterations in schizophrenia. Neurosci Lett. 2015;601:46–53.

    Article  CAS  Google Scholar 

  13. Roberts RC, Barksdale KA, Roche JK, Lahti AC. Decreased synaptic and mitochondrial density in the postmortem anterior cingulate cortex in schizophrenia. Schizophr Res. 2015;168:543–53.

    Article  CAS  Google Scholar 

  14. 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.

    Article  CAS  Google Scholar 

  15. Bennett MR. Schizophrenia: susceptibility genes, dendritic-spine pathology and gray matter loss. Prog Neurobiol. 2011;95:275–300.

    Article  CAS  Google Scholar 

  16. 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.

    Article  CAS  Google Scholar 

  17. Harrison PJ. Using our brains: the findings, flaws, and future of postmortem studies of psychiatric disorders. Biol Psychiatry. 2011;69:102–3.

    Article  Google Scholar 

  18. Radhakrishnan R, Skosnik PD, Ranganathan M, Naganawa M, Toyonaga T, Finnema S, et al. In vivo evidence of lower synaptic vesicle density in schizophrenia. Mol Psychiatry. 2021. https://doi.org/10.1038/s41380-41021-01184-41380. Online ahead of print.

  19. Mercier J, Archen L, Bollu V, Carre S, Evrard Y, Jnoff E, et al. Discovery of heterocyclic nonacetamide synaptic vesicle protein 2A (SV2A) ligands with single-digit nanomolar potency: opening avenues towards the first SV2A positron emission tomography (PET) ligands. ChemMedChem. 2014;9:693–8.

    Article  CAS  Google Scholar 

  20. Nabulsi NB, Mercier J, Holden D, Carre S, Najafzadeh S, Vandergeten MC, et al. Synthesis and preclinical evaluation of 11C-UCB-J as a PET tracer for imaging the synaptic vesicle glycoprotein 2A in the brain. J Nucl Med. 2016;57:777–84.

    Article  CAS  Google Scholar 

  21. Finnema SJ, Nabulsi NB, Eid T, Detyniecki K, Lin SF, Chen MK, et al. Imaging synaptic density in the living human brain. Sci Transl Med. 2016;8:348ra396.

    Article  Google Scholar 

  22. Finnema SJ, Nabulsi NB, Mercier J, Lin SF, Chen MK, Matuskey D, et al. Kinetic evaluation and test-retest reproducibility of [(11)C]UCB-J, a novel radioligand for positron emission tomography imaging of synaptic vesicle glycoprotein 2A in humans. J Cereb Blood Flow Metab. 2017;38:2041–52.

    Article  Google Scholar 

  23. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7.

    Article  Google Scholar 

  24. The Schizophrenia Working Group of the Psychiatric Genomics Consortium*, Ripke S, Walters JT, O’Donovan MC. Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia. MedRxiv [Preprint]. 2020. https://doi.org/10.1101/2020.1109.1112.20192922.

  25. Gusev A, Mancuso N, Won H, Kousi M, Finucane HK, Reshef Y, et al. Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights. Nat Genet. 2018;50:538–48.

    Article  CAS  Google Scholar 

  26. Huckins LM, Dobbyn A, Ruderfer DM, Hoffman G, Wang W, Pardinas AF, et al. Gene expression imputation across multiple brain regions provides insights into schizophrenia risk. Nat Genet. 2019;51:659–74.

    Article  CAS  Google Scholar 

  27. Hall LS, Medway CW, Pain O, Pardinas AF, Rees EG, Escott-Price V, et al. A transcriptome-wide association study implicates specific pre- and post-synaptic abnormalities in schizophrenia. Hum Mol Genet. 2020;29:159–67.

    Article  CAS  Google Scholar 

  28. Fromer M, Pocklington AJ, Kavanagh DH, Williams HJ, Dwyer S, Gormley P, et al. De novo mutations in schizophrenia implicate synaptic networks. Nature. 2014;506:179–84.

    Article  CAS  Google Scholar 

  29. Singh T, Neale BM, Daly MJ. Exome sequencing identifies rare coding variants in 10 genes which confer substantial risk for schizophrenia. MedRxiv [Preprint]. 2020. https://doi.org/10.1101/2020.1109.1118.20192815.

  30. 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.

    Article  CAS  Google Scholar 

  31. Glessner JT, Reilly MP, Kim CE, Takahashi N, Albano A, Hou C, et al. Strong synaptic transmission impact by copy number variations in schizophrenia. Proc Natl Acad Sci USA. 2010;107:10584–9.

    Article  CAS  Google Scholar 

  32. Pirooznia M, Wang T, Avramopoulos D, Valle D, Thomas G, Huganir RL, et al. SynaptomeDB: an ontology-based knowledgebase for synaptic genes. Bioinformatics. 2012;28:897–9.

    Article  CAS  Google Scholar 

  33. Hall J, Trent S, Thomas KL, O’Donovan MC, Owen MJ. Genetic risk for schizophrenia: convergence on synaptic pathways involved in plasticity. Biol Psychiatry. 2014;77:52–58.

    Article  Google Scholar 

  34. Kim M, Haney JR, Zhang P, Hernandez LM, Wang LK, Perez-Cano L, et al. Brain gene co-expression networks link complement signaling with convergent synaptic pathology in schizophrenia. Nat Neurosci. 2021;24:799–809.

    Article  CAS  Google Scholar 

  35. Wen Z, Nguyen HN, Guo Z, Lalli MA, Wang X, Su Y, et al. Synaptic dysregulation in a human iPS cell model of mental disorders. Nature. 2014;515:414–8.

    Article  CAS  Google Scholar 

  36. Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016;530:177–83.

    Article  CAS  Google Scholar 

  37. Yilmaz M, Yalcin E, Presumey J, Aw E, Ma M, Whelan CW, et al. Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice. Nat Neurosci. 2021;24:214–24.

    Article  CAS  Google Scholar 

  38. Deans PJM, Raval P, Sellers KJ, Gatford NJF, Halai S, Duarte RRR, et al. Psychosis risk candidate ZNF804A localizes to synapses and regulates neurite formation and dendritic spine structure. Biol Psychiatry. 2017;82:49–61.

    Article  CAS  Google Scholar 

  39. He E, Lozano MAG, Stringer S, Watanabe K, Sakamoto K, den Oudsten F, et al. MIR137 schizophrenia-associated locus controls synaptic function by regulating synaptogenesis, synapse maturation and synaptic transmission. Hum Mol Genet. 2018;27:1879–91.

    Article  CAS  Google Scholar 

  40. Yang CP, Li X, Wu Y, Shen Q, Zeng Y, Xiong Q, et al. Comprehensive integrative analyses identify GLT8D1 and CSNK2B as schizophrenia risk genes. Nat Commun. 2018;9:838.

    Article  Google Scholar 

  41. Kimoto S, Bazmi HH, Lewis DA. Lower expression of glutamic acid decarboxylase 67 in the prefrontal cortex in schizophrenia: contribution of altered regulation by Zif268. Am J Psychiatry. 2014;171:969–78.

    Article  Google Scholar 

  42. MacDonald ML, Garver M, Newman J, Sun Z, Kannarkat J, Salisbury R, et al. Synaptic proteome alterations in the primary auditory cortex of individuals with schizophrenia. JAMA Psychiatry. 2020;77:86–95.

    Article  Google Scholar 

  43. Onwordi EC, Halff EF, Whitehurst T, Mansur A, Cotel MC, Wells L, et al. Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats. Nat Commun. 2020;11:246.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was equally supported by the Key Research Project of Yunnan Province (202101AS070055) and the National Nature Science Foundation of China (U2102205). In addition, the study was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDPB17), the Major Science and Technology Projects of Henan Province (201300310200 to X-JL), the Distinguished Young Scientists Grant of Yunnan Province (202001AV070006), the Innovative Research Team of Science and Technology Department of Yunnan Province (2019HC004), the Western Light Innovative Research Team of Chinese’s Academy of Sciences, and the National Nature Science Foundation of China (81971252, U1904130, 31970561, 82171498).

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Authors and Affiliations

  1. Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453002, China

    Wenqiang Li & Luxian Lv

  2. Henan Key Lab of Biological Psychiatry, International Joint Research Laboratory for Psychiatry and Neuroscience of Henan, Xinxiang Medical University, Xinxiang, Henan, 453002, China

    Wenqiang Li & Luxian Lv

  3. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650204, China

    Xiong-Jian Luo

  4. Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China

    Xiong-Jian Luo

  5. Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan, 650204, China

    Xiong-Jian Luo

  6. KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650204, China

    Xiong-Jian Luo

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X-JL, WQL, and LXL wrote the manuscript. All authors revised the manuscript critically and approved the final version.

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Li, W., Lv, L. & Luo, XJ. In vivo study sheds new light on the dendritic spine pathology hypothesis of schizophrenia. Mol Psychiatry 27, 1866–1868 (2022). https://doi.org/10.1038/s41380-022-01449-2

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