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Hippocampal subfield transcriptome analysis in schizophrenia psychosis

Molecular Psychiatry volume 26, pages 2577–2589 (2021)Cite this article

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Abstract

We have previously demonstrated functional and molecular changes in hippocampal subfields in individuals with schizophrenia (SZ) psychosis associated with hippocampal excitability. In this study, we use RNA-seq and assess global transcriptome changes in the hippocampal subfields, DG, CA3, and CA1 from individuals with SZ psychosis and controls to elucidate subfield-relevant molecular changes. We also examine changes in gene expression due to antipsychotic medication in the hippocampal subfields from our SZ ON- and OFF-antipsychotic medication cohort. We identify unique subfield-specific molecular profiles in schizophrenia postmortem samples compared with controls, implicating astrocytes in DG, immune mechanisms in CA3, and synaptic scaling in CA1. We show a unique pattern of subfield-specific effects by antipsychotic medication on gene expression levels with scant overlap of genes differentially expressed by SZ disease effect versus medication effect. These hippocampal subfield changes serve to confirm and extend our previous model of SZ and can explain the lack of full efficacy of conventional antipsychotic medication on SZ symptomatology. With future characterization using single-cell studies, the identified distinct molecular profiles of the DG, CA3, and CA1 in SZ psychosis may serve to identify further potential hippocampal-based therapeutic targets.

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Fig. 1: Principal component analysis (PCA) plot of hippocampal RNA-seq data.
Fig. 2: DGEA and WGCNA characterization of dentate gyrus from individuals with SZ compared with controls.
Fig. 3: DGEA and WGCNA characterization of CA3 from individuals with SZ compared with controls.
Fig. 4: DGEA and WGCNA characterization of CA1 from individuals with SZ compared to controls.
Fig. 5: Gene expression changes in hippocampal subfields, DG, CA3, and CA1, in individuals with SZ either ON- or OFF-antipsychotic medication.

Code availability

Custom R codes and data to support the data analysis are available at https://github.com/konopkalab/Hippo_Subfields.

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Acknowledgements

We wish to thank the next of kin of the brain tissue donors who made this study possible, the Dallas County Medical Examiners’ Office, UT Southwestern Transplant Service and Willed Body Program for assistance with procurement of tissue. This project could not have been performed without the support and generosity of Dr Kenneth Altshuler. This project was performed with funding from the Stanton Sharp Distinguished Chair Endowment and T32 MH076690 Basic Science Training Program in Neurobiology of Mental Illness.

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Authors and Affiliations

  1. Division of Translational Neuroscience in Schizophrenia, Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Jessica Marie Perez, Kelly Gleason, Subroto Ghose, Chunfeng Tan & Carol A Tamminga

  2. Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX, 75390, USA

    Stefano Berto & Genevieve Konopka

  3. Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, 37673, Korea

    Tae-Kyung Kim

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  1. Jessica Marie Perez
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Perez, J.M., Berto, S., Gleason, K. et al. Hippocampal subfield transcriptome analysis in schizophrenia psychosis. Mol Psychiatry 26, 2577–2589 (2021). https://doi.org/10.1038/s41380-020-0696-6

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