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Linking proteomic alterations in schizophrenia hippocampus to NMDAr hypofunction in human neurons and oligodendrocytes

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Abstract

Glutamatergic neurotransmission dysfunction and the early involvement of the hippocampus have been proposed to be important aspects of the pathophysiology of schizophrenia. Here, we performed proteomic analysis of hippocampus postmortem samples from schizophrenia patients as well as neural cells—neurons and oligodendrocytes—treated with MK-801, an NMDA receptor antagonist. There were similarities in processes such as oxidative stress and apoptotic process when comparing hippocampus samples with MK-801-treated neurons, and in proteins synthesis when comparing hippocampus samples with MK-801-treated oligodendrocytes. This reveals that studying the effects of glutamatergic dysfunction in different neural cells can contribute to a better understanding of what it is observed in schizophrenia patients’ postmortem brains.

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Acknowledgements

The authors would like to thank all tissue donors and their families.

Funding

GSZ, GRO and DMS are supported by the São Paulo Research Foundation (FAPESP; grants 2018/14666-4, 2018/01410-1, 2017/25588-1, 2019/00098-7, 2018/01410-1) HIN is supported by CNPq and the São Paulo Research Foundation (FAPESP; grants 2017/50137-3, 2012/19278-6, and 2013/08216-2).

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Authors and Affiliations

  1. Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil

    Giuliana S. Zuccoli, Guilherme Reis-de-Oliveira & Daniel Martins-de-Souza

  2. Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo (USP), São Paulo, Brazil

    Bruna Garbes & Helder I. Nakaya

  3. Department of Psychiatry and Psychotherapy, Ludwig Maximillian University of Munich (LMU), Munich, Germany

    Peter Falkai & Andrea Schmitt

  4. Instituto Nacional de Biomarcadores Em Neuropsiquiatria (INBION), Conselho Nacional de Desenvolvimento Científico E Tecnológico, São Paulo, Brasil

    Daniel Martins-de-Souza

  5. Experimental Medicine Research Cluster (EMRC), University of Campinas, Campinas, Brazil

    Daniel Martins-de-Souza

  6. D’Or Institute for Research and Education (IDOR), São Paulo, Brazil

    Daniel Martins-de-Souza

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  1. Giuliana S. Zuccoli
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  2. Guilherme Reis-de-Oliveira
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  3. Bruna Garbes
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  4. Peter Falkai
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  5. Andrea Schmitt
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  6. Helder I. Nakaya
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  7. Daniel Martins-de-Souza
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Contributions

GSZ wrote the manuscript and made part of the data analysis, helped by GRO. DMS conceived and supervised the study and executed LC–MS/MS analyses. HIN headed data analysis, helped by BS. AS and PF provided brain tissue samples and followed the study development.

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Correspondence to Helder I. Nakaya or Daniel Martins-de-Souza.

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Supplementary Information

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406_2021_1248_MOESM1_ESM.xlsx

Supplementary Table 5 List of the pathways found altered in hippocampus samples (CA2/3), MK-801-treated oligodendrocytes (Oligodendrocytes) and MK-801-treated neurons (Neurons). X marks for the alteration in each condition, considering FDR < 0.05 (XLSX 12 KB)

Supplementary Table 1 Clinical data of schizophrenia patients and healthy controls (XLSX 12 KB)

Supplementary Table 2 Proteins differentially expressed in schizophrenia hippocampus (CA2/3) (DOCX 30 KB)

Supplementary Table 3 Proteins differentially expressed in MK-801-treated oligodendrocytes (DOCX 22 KB)

Supplementary Table 4 Proteins differentially expressed in MK-801-treated neurons (DOCX 18 KB)

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Zuccoli, G.S., Reis-de-Oliveira, G., Garbes, B. et al. Linking proteomic alterations in schizophrenia hippocampus to NMDAr hypofunction in human neurons and oligodendrocytes. Eur Arch Psychiatry Clin Neurosci 271, 1579–1586 (2021). https://doi.org/10.1007/s00406-021-01248-w

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