Abstract Elevated pro-inflammatory cytokines and increased macrophage densities have been found in a subgroup (~30-40%) of schizophrenia and bipolar disorder brains. However, the extent to which neuroinflammation influences the blood-brain barrier (BBB) in these serious mental illnesses has not been determined. Here, we measured multiple types of molecules related to BBB function in the ventral midbrain including 1) chemokines and macrophage markers; 2) endothelial cell-associated markers (adhesion molecules, tight junction proteins, and basement membrane proteins); in people with schizophrenia (n=35), or bipolar disorder (n=35) compared to controls (n=33). All cases were defined as “high” or “low” inflammatory status. Both mRNA and protein levels of macrophage chemokine (CCL2) and scavenger receptor (CD163) were significantly elevated in the neuroinflammatory schizophrenia (high) compared to all the low inflammatory subgroups. We found elevated mRNA levels of adhesion molecules (ICAM1 and PECAM1) in schizophrenia and bipolar disorder high inflammatory subgroups, however, PECAM1 protein was only elevated in schizophrenia. Surprisingly, ICAM protein was decreased in the bipolar disorder high inflammatory subgroup. The bipolar disorder group also had lower collagen IV (ColIV) protein levels. Levels of the mRNA encoding the tight junction protein claudin-5 (CLDN5) was elevated in both schizophrenia and bipolar disorder high inflammatory subgroups, while occludin (OCLN) mRNA levels were decreased in schizophrenia, especially in the high inflammatory subgroup. Through immunohistochemistry for CLDN5 revealed increased fragmented blood vessels with bursts of CLDN5+ processes surrounding and appearing to emanate from endothelial cells in schizophrenia and bipolar disorder high inflammation. Collectively, the high inflammatory subgroups of individuals with schizophrenia or bipolar disorder display more signs of macrophage chemoattraction which appeared linked to changes in the BBB, including alterations in adhesion molecules and tight junction proteins. However, schizophrenia and bipolar disorder have distinct molecular signatures of BBB pathology in the midbrain.
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.
Abstract The primate postnatal subventricular zone (SVZ) lies under the ventrolateral borders of the lateral ventricles as a discrete region of cells with gliogenic and neurogenic capacity regulated by ErbB receptors. However, the specific role of each ErbB subtype in SVZ cell development remains unclear, particularly in the human brain. The postnatal spatial and temporal expression profile of ErbB subtypes in the human brain may provide valuable insight into their distinct functions in the SVZ following birth. Hence, we examined the expression profile of ErbB1, ErbB2, ErbB3 and ErbB4 mRNA in the SVZ of human postmortem brains from neonates, infants, toddlers, school age subjects, adolescents, young adults and adults using in situ hybridization. SVZ transcript levels of ErbB1 and ErbB4 were highest in neonates and diminished with age. SVZ ErbB4 mRNA quantities significantly decreased by >85% to almost undetectable levels after the first year of life, while SVZ ErbB1 transcript levels displayed more gradual reductions, stabilizing to ∼30–40% of neonate levels after the age of 5 years. In the neonate and infant SVZ, ErbB4 mRNA was localized to cell clusters resembling migratory neuroblast aggregates whereas ErbB1 mRNA was expressed in cells along but not within these clusters. ErbB2 mRNA appeared to be constantly expressed in the human SVZ at all postnatal ages as opposed to ErbB3 transcripts, which were not detected in the human SVZ at any age following birth. These findings suggest that ErbB1 and ErbB4 may play more salient roles than ErbB2 and ErbB3 in mediating early postnatal neurodevelopmental events. In addition, ErbB1‐ and ErbB4‐immunoreactive cells and fibers were extensive throughout the human infant SVZ, but did not appear to overlap with PSA‐NCAM‐immunopositive clusters. The restriction of robust SVZ ErbB4 expression to neonate and infant age groups may indicate that SVZ‐derived ErbB4‐dependent postnatal neuronal development is most extensive within a narrow time frame early after birth.
Abstract In the human neocortex, progressive synaptogenesis in early postnatal life is followed by a decline in synaptic density, then stability from adolescence until middle age. No comparable data are available in the hippocampus. In this study, the integral synaptic vesicle protein synaptophysin, measured immunoautoradiographically, was used as an index of synaptic terminal abundance in the hippocampal formation of 37 subjects from 5 weeks to 86 yr old, divided into 4 age groups (10 infants, 15 adolescents/young adults, 6 adults, and 6 elderly). In all hippocampal subfields, synaptophysin was lowest in infancy, but did not differ significantly between the older age groups, except in dentate gyrus (DG) where the rise was delayed until adulthood. A similar developmental profile was found in the rat hippocampus. We also measured synaptophysin mRNA in the human subjects and found no age‐related changes, except in parahippocampal gyrus wherein the mRNA declined from infancy to adolescence, and again in old age. The synaptophysin protein data demonstrate a significant presynaptic component to human postnatal hippocampal development. In so far as synaptophysin abundance reflects synaptic density, the findings support an increase in hippocampal and parahippocampal synapse formation during early childhood, but provide no evidence for adolescent synaptic pruning. The mRNA data indicate that the maturational increases in synaptophysin protein are either translational rather than transcriptional in origin, or else are secondary to mRNA increases in neurons, the cell bodies of which lie outside the hippocampal formation. Published 2006 Wiley‐Liss, Inc.
