Shiwaku_2023_Brain.Behav.Immun__

The molecular pathological mechanisms underlying schizophrenia remain unclear; however, genomic analysis has identified genes encoding important risk molecules. One such molecule is neurexin 1alpha (NRXN1alpha), a presynaptic cell adhesion molecule. In addition, novel autoantibodies that target the nervous system have been found in patients with encephalitis and neurological disorders. Some of these autoantibodies inhibit synaptic antigen molecules. Studies have examined the association between schizophrenia and autoimmunity; however, the pathological data remain unclear. Here, we identified a novel autoantibody against NRXN1alpha in patients with schizophrenia (n=2.1%) in a Japanese cohort (n=387). None of the healthy control participants (n=362) were positive for anti-NRXN1alpha autoantibodies. Anti-NRXN1alpha autoantibodies isolated from patients with schizophrenia inhibited the molecular interaction between NRXN1alpha and Neuroligin 1 (NLGN1) and between NRXN1alpha and Neuroligin 2 (NLGN2). Additionally, these autoantibodies reduced the frequency of the miniature excitatory postsynaptic current in the frontal cortex of mice. Administration of anti-NRXN1alpha autoantibodies from patients with schizophrenia into the cerebrospinal fluid of mice reduced the number of spines/synapses in the frontal cortex and induced schizophrenia-related behaviors such as reduced cognition, impaired pre-pulse inhibition, and reduced social novelty preference. These changes were improved through the removal of anti-NRXN1alpha autoantibodies from the IgG fraction of patients with schizophrenia. These findings demonstrate that anti-NRXN1alpha autoantibodies transferred from patients with schizophrenia cause schizophrenia-related pathology in mice. Removal of anti-NRXN1alpha autoantibodies may be a therapeutic target for a subgroup of patients who are positive for these autoantibodies.