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

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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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.

Corresponding authors

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

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Authors have nothing to disclose.

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 (2021). https://doi.org/10.1007/s00406-021-01248-w

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Keywords

  • Proteome
  • Hippocampus
  • Neurons
  • Oligodendrocytes
  • MK-801