Project Summary There is mounting evidence that the immune system plays a causal role in the pathogenesis of psychiatric disorders in a subset of patient population: 1) Patients with anti-NMDAR encephalitis, caused by autoantibodies against NMDAR1 (NMDAR1-AB), are often first admitted into psychiatric centers due to severe psychiatric symptoms. 2) Patients with multiple sclerosis (MS), a neuroinflammatory/autoimmune disease in the central nervous system (CNS), have 95% co-morbidity with psychiatric disorders including depression, hallucination, and delusion. Autoantibodies against myelin and NMDAR1-AB contribute to demyelination and psychiatric symptoms in MS patients. 3) Patients with systemic lupus erythematosus (SLE), an autoimmune disease, display 65% co-morbidity with mood disorders. A subset of anti-DNA antibodies in SLE patients cross-react with human NMDAR2A and NMDAR2B receptors and associate with the development of psychiatric symptoms. Taken together, anti-NMDAR autoantibodies originating from either CNS or peripheral systems can generate a broad spectrum of psychiatric symptoms when present in CNS. Genetic evidence linking the immune system with ?pure? psychiatric disorders was provided by GWAS studies. Major histocompatibility complex, essential for antigen presentation, is the strongest locus associated with schizophrenia in the general population of patients. As direct evidence, serum NMDAR1-AB were reported to be in ~10% of patients with schizophrenia and other psychiatric disorders in the general population vs in 0.4% of healthy controls. Interestingly, two schizophrenia patients with the highest titers of NMDAR1-AB were re- classified as anti-NMDAR encephalitis after the study, indicating a practical difficulty in separating pure psychiatric disorders from anti-NMDAR encephalitis in some cases. However, another independent study found that ~10% of people, either healthy controls or psychiatric patients, have NMDAR1-AB in their serum. The authors suggested that blood-brain barrier (BBB) integrity plays a key role preventing the development of psychiatric disorders from circulating NMDAR1-AB. While the two studies have a discrepancy in the prevalence of NMDAR1-AB in healthy controls, which remains to be resolved, both studies found that ~10% of psychiatric patients have a range of NMDAR1-AB titers in serum. In this application, we hypothesize that chronic neuroinflammation facilitates NMDAR1-AB generation in inflammatory brain tissue or breaks BBB for pre-existing NMDAR1-AB to shuttle between CNS and circulation and thereby contributes to the pathogenesis of psychiatric disorders. In Aim1, we will investigate generation of NMDAR1-AB from neuroinflammation triggered by chronic activation of the innate immune system in the CNS and associated behavioral abnormalities. In Aim 2, we will investigate effects of microglial activation on BBB permeability of circulating antibodies and peripheral immune cell infiltration. If our hypothesis is correct, neuroinflammation, BBB breakdown, and NMDAR1-AB may be used as biomarkers to assess synaptic autoimmunity.