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

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.