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Reduced adult neurogenesis is associated with increased macrophages in the subependymal zone in schizophrenia

Abstract

Neural stem cells in the human subependymal zone (SEZ) generate neuronal progenitor cells that can differentiate and integrate as inhibitory interneurons into cortical and subcortical brain regions; yet the extent of adult neurogenesis remains unexplored in schizophrenia and bipolar disorder. We verified the existence of neurogenesis across the lifespan by chartering transcriptional alterations (2 days–103 years, n = 70) and identifying cells indicative of different stages of neurogenesis in the human SEZ. Expression of most neural stem and neuronal progenitor cell markers decreased during the first postnatal years and remained stable from childhood into ageing. We next discovered reduced neural stem and neuronal progenitor cell marker expression in the adult SEZ in schizophrenia and bipolar disorder compared to controls (n = 29–32 per group). RNA sequencing identified increased expression of the macrophage marker CD163 as the most significant molecular change in schizophrenia. CD163+ macrophages, which were localised along blood vessels and in the parenchyma within 10 µm of neural stem and progenitor cells, had increased density in schizophrenia but not in bipolar disorder. Macrophage marker expression negatively correlated with neuronal progenitor marker expression in schizophrenia but not in controls or bipolar disorder. Reduced neurogenesis and increased macrophage marker expression were also associated with polygenic risk for schizophrenia. Our results support that the human SEZ retains the capacity to generate neuronal progenitor cells throughout life, although this capacity is limited in schizophrenia and bipolar disorder. The increase in macrophages in schizophrenia but not in bipolar disorder indicates that immune cells may impair neurogenesis in the adult SEZ in a disease-specific manner.

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Fig. 1: Expression of neurogenesis markers sharply declined in the human SEZ during the first postnatal years and remained stable from childhood into ageing.
Fig. 2: Neural stem and progenitor cells were present in the adult SEZ.
Fig. 3: Decreased expression of neurogenesis markers coincided with reduced trophic support and increased inflammation in the adult SEZ in psychiatric disorders.
Fig. 4: Increased presence of perivascular macrophages was intrinsic to the adult SEZ in schizophrenia.
Fig. 5: Polygenic risk scores for schizophrenia showed diagnostic group differences and relationships to neurogenesis and macrophage marker expression in the adult SEZ.

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Acknowledgements

This work was funded by the NSW Ministry of Health, Office of Health and Medical Research. CSW is a recipient of a National Health and Medical Research Council (Australia) Principal Research Fellowship (1117079). JMF is the recipient of the Janette Mary O’Neil Research Fellowship. GMH is a recipient of a National Health and Medical Research Council (Australia) Senior Leadership Fellowship (1117079). Tissues were received from the New South Wales Brain Tissue Resource Centre at the University of Sydney and the Sydney Brain Bank at Neuroscience Research Australia which are supported by The University of New South Wales, Neuroscience Research Australia and Schizophrenia Research Institute. Research reported in this publication was supported by the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health under Award Number R28AA012725. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Conceptualisation, CW, GB, MJW and CSW; Methodology, CW, HFN, MB, JMF, RS, GB, MJW and CSW; Investigation, CW, HFN, MB, JMF, RS, GB and MJW; Validation, CW, HFN and RS; Formal analysis, CW, HFN, MB, JMF, RS and GB; Writing—Original draft, CW, HFN, JMF and CSW; Writing—Review & Editing, CW, HFN, MB, JMF, RS, GB, MP, GMH, MJW and CSW; Funding acquisition, CW, GB and CSW; Resources, MB, GB, GMH, MJW and CSW; Supervision, CW, MB, JMF, GB and CSW.

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Correspondence to Cynthia Shannon Weickert.

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CSW is on an advisory board for Lundbeck, Australia Pty Ltd and in collaboration with Astellas Pharma Inc., Japan. All other authors have no competing interests to disclose.

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Weissleder, C., North, H.F., Bitar, M. et al. Reduced adult neurogenesis is associated with increased macrophages in the subependymal zone in schizophrenia. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01149-3

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