The study of brain-immune interactions has contributed to a paradigm shift in the understanding of the pathophysiology of mental disorders and has provided new insights into their prevention and treatment. Notably, the blood-brain barrier (BBB) functions to restrict interactions between the brain and periphery, limiting the influence of peripheral inflammation on the brain. However, increasing evidence indicates impairment of the BBB in conditions like autism and schizophrenia, which combined with the consistently elevated levels of the cytokines IL-6 and IL-1β, could potentially affect the ontology and outcome of neuropsychiatric disease. Thus, this proposal addresses the connectivity of peripheral-neuroinflammation through brain vasculature, its impact on behavior, and how they interact in response to an environmental “second hit”. We will study this interplay within the brain- immune axis in the context of genetic susceptibility to neuropsychiatric disease. Besides providing a compelling rationale to devise immune therapeutic strategies, the demonstration of a brain-immune link will be crucial for understanding the mechanisms driving disease processes in mental illness. Our proposal makes use of a model of human genetic susceptibility to neuropsychiatric disease conferred by the 22q11.2 deletion syndrome (22qDS). Based on the inclusion of genes that could affect BBB function, our previous work demonstrated BBB compromise in 22qDS, a phenotype recapitulated in the mouse model of the disease. Furthermore, our preliminary data indicate that adult 22qDS model mice have elevated levels of IL-6 and IL-1β, cytokines that promote T cell responses characterized by the expression of the pro-inflammatory cytokine IL-17. We find enhanced IL-17-mediated inflammatory activation in the brain, modeling the exaggerated IL-17 responses seen in 22qDS and neuropsychiatric patients. Notably, 22qDS mice also exhibit behavioral deficits reminiscent of those seen in human patients. Ther