Abstract
Genetic and epidemiological studies suggest that autoimmunity may underlie schizophrenia. A key component of autoimmune pathology is the presence of autoantibodies. Recently, novel synaptic autoantibodies have been identified in patients with autoimmune encephalitis, leading to the concept of autoimmune psychosis-an acute psychosis associated with positive autoantibodies. Based on these backgrounds, we hypothesized the existence of unidentified synaptic autoantibodies contributing to the pathology of schizophrenia and conducted investigations to identify them. Consequently, we discovered novel autoantibodies targeting synaptic adhesion molecules NCAM1 and NRXN1. We demonstrated that when these autoantibodies were isolated from patients and introduced into the cerebrospinal fluid of mice, they disrupted the binding of NCAM1 and NRXN1 at synapses. This interference led to a reduction in synaptic density and spines, resulting in impaired cognitive function, abnormal prepulse inhibition, and reduced sociability. These findings suggest that the autoantibodies detected in schizophrenia patients could be pathogenic and represent potential therapeutic targets. Furthermore, these autoantibodies may serve as biomarkers to identify subgroups of schizophrenia patients who could benefit from such treatments.
