Single-nucleus RNA sequencing of the midbrain blood-brain barrier cells in schizophrenia
Background: The increased inflammatory state observed in schizophrenia post-mortem brain and midbrain tissue [1-5] may have detrimental consequences on the brain vasculature of patients with schizophrenia. On the other hand, intrinsic alterations in the brain vasculature of schizophrenia patients ma...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-04-01
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| Series: | Journal of Affective Disorders Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666915323000975 |
| _version_ | 1797854499474243584 |
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| author | Sofía Puvogel Astrid Alsema Laura Kracht Maree Webster Cynthia Weickert-Shannon Iris E.C. Sommer Bart J.L. Eggen |
| author_facet | Sofía Puvogel Astrid Alsema Laura Kracht Maree Webster Cynthia Weickert-Shannon Iris E.C. Sommer Bart J.L. Eggen |
| author_sort | Sofía Puvogel |
| collection | DOAJ |
| description | Background: The increased inflammatory state observed in schizophrenia post-mortem brain and midbrain tissue [1-5] may have detrimental consequences on the brain vasculature of patients with schizophrenia. On the other hand, intrinsic alterations in the brain vasculature of schizophrenia patients may impair toxin efflux and favour the ingression of toxic material and immune cells into the central nervous system, leading to neuroinflammation. Evidence derived from blood and cerebrospinal fluid measurements indicated increased levels of adhesion molecules, such as sP-selectin and sICAM, in schizophrenia [6-8], which may favour the ingression of immune cells into the brain, and higher levels of albumin in CSF as compared to controls, suggesting increased BBB permeability in schizophrenia patients [6, 7, 9]. However, the proper functioning of the BBB involves a variety of cell types, and it is not known which cell type(s) of the BBB may be particularly affected in schizophrenia. Methods: We combined a fluorescence activated sorting isolation strategy with single-nucleus RNA sequencing (snRNAseq) to characterize the cells of the BBB in the midbrain of 15 schizophrenia donors and 14 matched controls, from the well-characterized Stanley Brain Collection. The cases used for the present study were previously grouped into high and low inflammation cases, based on the expression of inflammatory cytokines in their cortical grey matter, and 4 out of the 15 schizophrenia cases were assigned to the cortical high-inflammation group [10]. The different cell types of the BBB were identified with unbiased cluster analysis of nuclear transcriptomic profiles and annotated based on the expression of cell type-specific marker genes. Subclustering analysis, gene set enrichment and comparisons with previously published datasets were carried out to identify sub-populations among the main BBB cell types. We compared the transcriptomic profiles of the major BBB cell types between schizophrenia and controls. In addition, the relative abundance of the main BBB cell types and sub-populations was compared between the diagnoses, using generalized linear modeling. Results: We did not identify changes in the relative abundance of the major BBB cell types, nor in the sub-populations, associated with schizophrenia. However, we identified 14 differentially expressed genes in the cells of the BBB in schizophrenia as compared to controls, including genes that have previously been related to schizophrenia, such as FOXP2 and PDE4D. These transcriptional changes associated with schizophrenia were limited to the ependymal cells and pericytes. Additionally, we detected a sub-population of protoplasmic astrocytes enriched in the high inflammation schizophrenia subgroup. Genes more abundantly expressed in these schizophrenia-related protoplasmic astrocytes were associated with glutamatergic synaptic function rather than with inflammation. Conclusion: Our overall diagnostic results suggest the relative abundance of the BBB cell types and cellular sub-populations remains unaltered in schizophrenia pathology. Nonetheless, transcriptional changes in the midbrain BBB cells associated with schizophrenia are found, but are limited and are specific to two cell types, the ependymal and pericytes. In addition, the high inflammatory status observed in a subgroup of the patients may be interfering with the normal activities of protoplasmic astrocytes, possibly associated with midbrain dopamine and glutamate neurons. |
| first_indexed | 2024-04-09T20:08:09Z |
| format | Article |
| id | doaj.art-e7076bed0fb5445fb298a54fb87aa7e6 |
| institution | Directory Open Access Journal |
| issn | 2666-9153 |
| language | English |
| last_indexed | 2024-04-09T20:08:09Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Affective Disorders Reports |
| spelling | doaj.art-e7076bed0fb5445fb298a54fb87aa7e62023-04-01T08:51:58ZengElsevierJournal of Affective Disorders Reports2666-91532023-04-0112100558Single-nucleus RNA sequencing of the midbrain blood-brain barrier cells in schizophreniaSofía Puvogel0Astrid Alsema1Laura Kracht2Maree Webster3Cynthia Weickert-Shannon4Iris E.C. Sommer5Bart J.L. Eggen6Department of Biomedical Sciences of Cells and Systems, section Cognitive Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Biology, Faculty of Sciences, Universidad de Chile, Santiago, Chile; Presenting author: Sofía Puvogel, University Medical Center Groningen, Petrus Campersingel, Groningen, NetherlandsDepartment of Biomedical Sciences of Cells and Systems, section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, Groningen, The NetherlandsDepartment of Biomedical Sciences of Cells and Systems, section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, Groningen, The NetherlandsStanley Medical Research Institute, Laboratory of Brain Research, Rockville, Maryland, USASchool of Psychiatry, University of New South Wales, Sydney, NSW, AustraliaDepartment of Biomedical Sciences of Cells and Systems, section Cognitive Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Centre Utrecht, Utrecht, The NetherlandsDepartment of Biomedical Sciences of Cells and Systems, section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, Groningen, The NetherlandsBackground: The increased inflammatory state observed in schizophrenia post-mortem brain and midbrain tissue [1-5] may have detrimental consequences on the brain vasculature of patients with schizophrenia. On the other hand, intrinsic alterations in the brain vasculature of schizophrenia patients may impair toxin efflux and favour the ingression of toxic material and immune cells into the central nervous system, leading to neuroinflammation. Evidence derived from blood and cerebrospinal fluid measurements indicated increased levels of adhesion molecules, such as sP-selectin and sICAM, in schizophrenia [6-8], which may favour the ingression of immune cells into the brain, and higher levels of albumin in CSF as compared to controls, suggesting increased BBB permeability in schizophrenia patients [6, 7, 9]. However, the proper functioning of the BBB involves a variety of cell types, and it is not known which cell type(s) of the BBB may be particularly affected in schizophrenia. Methods: We combined a fluorescence activated sorting isolation strategy with single-nucleus RNA sequencing (snRNAseq) to characterize the cells of the BBB in the midbrain of 15 schizophrenia donors and 14 matched controls, from the well-characterized Stanley Brain Collection. The cases used for the present study were previously grouped into high and low inflammation cases, based on the expression of inflammatory cytokines in their cortical grey matter, and 4 out of the 15 schizophrenia cases were assigned to the cortical high-inflammation group [10]. The different cell types of the BBB were identified with unbiased cluster analysis of nuclear transcriptomic profiles and annotated based on the expression of cell type-specific marker genes. Subclustering analysis, gene set enrichment and comparisons with previously published datasets were carried out to identify sub-populations among the main BBB cell types. We compared the transcriptomic profiles of the major BBB cell types between schizophrenia and controls. In addition, the relative abundance of the main BBB cell types and sub-populations was compared between the diagnoses, using generalized linear modeling. Results: We did not identify changes in the relative abundance of the major BBB cell types, nor in the sub-populations, associated with schizophrenia. However, we identified 14 differentially expressed genes in the cells of the BBB in schizophrenia as compared to controls, including genes that have previously been related to schizophrenia, such as FOXP2 and PDE4D. These transcriptional changes associated with schizophrenia were limited to the ependymal cells and pericytes. Additionally, we detected a sub-population of protoplasmic astrocytes enriched in the high inflammation schizophrenia subgroup. Genes more abundantly expressed in these schizophrenia-related protoplasmic astrocytes were associated with glutamatergic synaptic function rather than with inflammation. Conclusion: Our overall diagnostic results suggest the relative abundance of the BBB cell types and cellular sub-populations remains unaltered in schizophrenia pathology. Nonetheless, transcriptional changes in the midbrain BBB cells associated with schizophrenia are found, but are limited and are specific to two cell types, the ependymal and pericytes. In addition, the high inflammatory status observed in a subgroup of the patients may be interfering with the normal activities of protoplasmic astrocytes, possibly associated with midbrain dopamine and glutamate neurons.http://www.sciencedirect.com/science/article/pii/S2666915323000975 |
| spellingShingle | Sofía Puvogel Astrid Alsema Laura Kracht Maree Webster Cynthia Weickert-Shannon Iris E.C. Sommer Bart J.L. Eggen Single-nucleus RNA sequencing of the midbrain blood-brain barrier cells in schizophrenia Journal of Affective Disorders Reports |
| title | Single-nucleus RNA sequencing of the midbrain blood-brain barrier cells in schizophrenia |
| title_full | Single-nucleus RNA sequencing of the midbrain blood-brain barrier cells in schizophrenia |
| title_fullStr | Single-nucleus RNA sequencing of the midbrain blood-brain barrier cells in schizophrenia |
| title_full_unstemmed | Single-nucleus RNA sequencing of the midbrain blood-brain barrier cells in schizophrenia |
| title_short | Single-nucleus RNA sequencing of the midbrain blood-brain barrier cells in schizophrenia |
| title_sort | single nucleus rna sequencing of the midbrain blood brain barrier cells in schizophrenia |
| url | http://www.sciencedirect.com/science/article/pii/S2666915323000975 |
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