Neuropsychiatric disorders are increasingly associated with neuroinflammatory processes. The blood-brain barrier (BBB) is a critical modulator of peripheral inflammatory influences on brain development and function. PIs Jorge Alvarez, a neuroimmunologist with expertise in the BBB, and Stewart Anderson, a developmental neurobiologist with expertise in mechanisms of neuropsychiatric disorders, have recently demonstrated that the BBB is compromised in a relatively common genetic cause of neuropsychiatric illness, the 22q11.2 deletion syndrome (22qDS). While this finding in induced pluripotent stem cell (iPSC)-derived BBB-like cells (iBBB) and in 22qDS model mice was initially ascribed mainly to haploinsufficiency of the BBB-enriched tight junction protein claudin-5, work from the Anderson lab and others has also demonstrated that 22qDS is associated with mitochondrial energetic compromise in various cell types. Since mitochondrial energetics are also necessary for optimal BBB function, the PIs initiated experiments to determine whether mitochondrial energetics of the BBB are compromised in 22qDS, whether this compromise is likely to influence BBB dysfunction in this disorder, and whether correction of mitochondrial weakness improves BBB dysfunction in 22qDS. Remarkably, our preliminary data strongly suggest that all three scenarios are true. If so, BBB energetics could be an underexplored therapeutic target for neurodevelopmental and neurodegenerative disorders that involve inflammation. Here, we propose to study the synergistic influences of structural and energetic compromise on BBB function. Building upon our previous findings in iPSC-derived neurons and transformed blood cells, which showed that 22qDS with schizophrenia (SZ) exhibits weaker mitochondrial energetics compared to 22qDS without SZ or non-deleted controls, in Aim 1, we will investigate whether this association of mitochondrial weakness and the presence of SZ in 22qDS extends to iBBB cells. We will also