Discovery of novel blood–brain barrier neuropathology in schizophrenia and bipolar disorder midbrain

Abstract

Elevated pro-inflammatory cytokines and increased macrophage densities have been found in ∼ 35–50 % of schizophrenia and bipolar disorder brains. However, the influence of neuroinflammation on the blood–brain barrier (BBB) in these serious mental illnesses remains unclear. Here, we measured and compared multiple BBB-associated molecules in the ventral midbrain, including chemokines, macrophage markers, adhesion molecules, tight junction proteins, and basement membrane proteins in people with schizophrenia (n = 35), or bipolar disorder (n = 34), and controls (n = 33), stratified by inflammatory status. Both mRNA and protein levels of macrophage chemokine (CCL2) and macrophage scavenger receptor (CD163) were significantly elevated in the neuroinflammatory schizophrenia (high) compared to all the low inflammatory subgroups. Adhesion molecule mRNAs (ICAM1 and PECAM1) were increased in both schizophrenia and bipolar disorder high inflammatory subgroups, but PECAM1 protein was only elevated in schizophrenia, while ICAM1 protein was decreased in bipolar disorder. We found lower collagen IV (ColIV) protein levels in bipolar disorder. Tight junction protein claudin-5 (CLDN5) mRNA was elevated in both schizophrenia and bipolar disorder high inflammatory subgroups, while occludin (OCLN) mRNA was decreased in schizophrenia, especially in the high inflammatory subgroup. CLDN5 immunostaining 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 subgroup. Collectively, the high inflammatory individuals in both schizophrenia and/or bipolar disorder display more signs of BBB alterations, including increased macrophage chemoattraction, changed adhesion molecules, and altered tight junction proteins, though they have distinct molecular signatures of BBB pathology in the midbrain.