A Preliminary Report: The Hippocampus and Surrounding Temporal Cortex of Patients With Schizophrenia Have Impaired Blood-Brain Barrier

Abstract

Though hippocampal volume reduction is a pathological hallmark of schizophrenia, the molecular pathway(s) responsible for this degeneration remains unknown. Recent reports have suggested the potential role of impaired blood-brain barrier (BBB) function in schizophrenia pathogenesis. However, direct evidence demonstrating an impaired BBB function is missing. In this preliminary study, we used immunohistochemistry and serum immunoglobulin G (IgG) antibodies to investigate the state of BBB function in formalin-fixed postmortem samples from the hippocampus and surrounding temporal cortex of patients with schizophrenia (n = 25) and controls without schizophrenia (n = 27) matched for age, sex, and race. Since a functional BBB prevents the extravasation of IgGs, detection of IgGs in the parenchyma is used as direct evidence of BBB breakdown. We also developed a semi-quantitative approach to quantify the extent of IgG leak and therein BBB breach. Analysis of our immunohistochemistry data demonstrated a significantly higher incidence of IgG leak in patients with schizophrenia compared to controls. Further, BBB permeability was significantly higher in advanced-age patients with schizophrenia than both advanced-age controls and middle-aged patients with schizophrenia. Male patients with schizophrenia also demonstrated a significant increase in IgG permeability compared to control males. Interestingly, the extravasated IgGs also demonstrated selective immunoreactivity for neurons. Based on these observations, we suggest that BBB dysfunction and IgG autoantibodies could be two key missing pathoetiological links underwriting schizophrenia hippocampal damage.

Potential Cross Talk between Autism Risk Genes and Neurovascular Molecules: A Pilot Study on Impact of Blood Brain Barrier Integrity

“…These are novel examples of potential interactions between neuronal-based and endothelial-based cell signaling which affects brain development ( Figure 13 ). In this regard, one can see parallels between inflammatory processes in autism and another genetically related developmental disorder, schizophrenia (SCZ) [ 155 , 156 ] In SCZ, inflammatory markers are associated with cortical expansion and impaired blood brain barrier function which correlates with symptom severity [ 157 , 158 ]. Using human induced pluripotent stem cells, SCZ-derived brain endothelial cells have decreased vasculogenesis and permeability, and decreased ZO-1 expression (tight junction protein) with altered cellular localization in the cytoplasm [ 159 ].…”

Universal method for the isolation of microvessels from frozen brain tissue: A proof-of-concept multiomic investigation of the neurovasculature

“…Because of its bipolar nature, dysfunction of the BBB can arise from, and be further aggravated by, either the CNS or peripheral compartments. Evidence of neurovascular dysfunction has similarly been observed in bipolar disorder ( Kamintsky et al, 2020 ), schizophrenia ( Kirkpatrick and Miller, 2013 ; Axelsson et al, 1982 ; Campana et al, 2023 ; Goldwaser et al, 2022 ), major depressive disorder ( Torres-Platas et al, 2014 ; Gal et al, 2023 ; Najjar et al, 2013 ), and Parkinson's disease ( Al-Bachari et al, 2020 ; Fowler et al, 2021 ).…”

Immune System and Brain/Intestinal Barrier Functions in Psychiatric Diseases: Is Sphingosine-1-Phosphate at the Helm?

“…These features can explain the heterogenous information about astrocytes in SZ. Studies have reported increased BBB permeability in temporal lobe structures, including the hippocampus, in postmortem samples of SZ [ 254 ]. As S1P modulates BBB permeability [ 181 ], further investigations are needed to explore the potential relationship between S1P and BBB dysfunction in SZ.…”