Disruption of the blood-brain barrier in 22q11.2 deletion syndrome

Abstract

Neuroimmune dysregulation is implicated in neuropsychiatric disorders including schizophrenia. As the blood-brain barrier is the immunological interface between the brain and the periphery, we investigated whether this vascular phenotype is intrinsically compromised in the most common genetic risk factor for schizophrenia, the 22q11.2 deletion syndrome (22qDS). Blood-brain barrier like endothelium differentiated from human 22qDS+schizophrenia-induced pluripotent stem cells exhibited impaired barrier integrity, a phenotype substantiated in a mouse model of 22qDS. The proinflammatory intercellular adhesion molecule-1 was upregulated in 22qDS+schizophrenia-induced blood-brain barrier and in 22qDS mice, indicating compromise of the blood-brain barrier immune privilege. This immune imbalance resulted in increased migration/activation of leucocytes crossing the 22qDS+schizophrenia blood-brain barrier. We also found heightened astrocyte activation in murine 22qDS, suggesting that the blood-brain barrier promotes astrocyte-mediated neuroinflammation. Finally, we substantiated these findings in post-mortem 22qDS brain tissue. Overall, the barrier-promoting and immune privilege properties of the 22qDS blood-brain barrier are compromised, and this might increase the risk for neuropsychiatric disease.

Keywords: 22q11.2 deletion syndrome; blood−brain barrier; neuroinflammation; schizophrenia.