Single-nucleus RNA sequencing of the midbrain blood-brain barrier cells in schizophrenia reveals subtle transcriptional changes with overall preservation of cellular proportions and phenotypes

Abstract

The midbrain is an important brain region for the study of schizophrenia in view of its reported dopamine pathophysiology and observed neuroimmune changes associated with schizophrenia. Besides the dopaminergic system, the midbrain contains other cell types that may be involved in schizophrenia pathophysiology. The neurovascular hypothesis of schizophrenia postulates that both the neurovasculature structure and the functioning of the blood-brain barrier (BBB) are compromised in schizophrenia. In the present study, potential alteration in the BBB of patients with schizophrenia was investigated by single-nucleus RNA sequencing of post-mortem midbrain tissue (14 schizophrenia cases and 15 matched controls). 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. This schizophrenia cohort was previously stratified into “high inflammation” and “low inflammation” cases, based on cortical inflammation-related transcripts. 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. In summary, transcriptional changes in the cells of the BBB in schizophrenia are limited and specific. In addition, inflammation may be affecting the function of astrocytes in a subgroup of schizophrenia patients, and thereby contribute to schizophrenia pathophysiology.