Analyzing schizophrenia-related phenotypes in mice caused by autoantibodies against NRXN1? in schizophrenia

The molecular pathological mechanisms underlying schizophrenia remain unclear; however, genomic analysis has identified genes encoding important risk molecules. One such molecule is neurexin 1 alpha (NRXN1 alpha), a pre -synaptic 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 NRXN1 alpha 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-NRXN1 alpha autoantibodies. Anti-NRXN1 alpha autoantibodies isolated from patients with schizophrenia inhibited the molecular interaction between NRXN1 alpha and Neuroligin 1 (NLGN1) and between NRXN1 alpha 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-NRXN1 alpha 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 in-hibition, and reduced social novelty preference. These changes were improved through the removal of anti-NRXN1 alpha autoantibodies from the IgG fraction of patients with schizophrenia. These findings demonstrate that anti-NRXN1 alpha autoantibodies transferred from patients with schizophrenia cause schizophrenia-related pathology in mice. Removal of anti-NRXN1 alpha autoantibodies may be a therapeutic target for a subgroup of patients who are positive for these autoantibodies.

Automated summary

This study identified a novel autoantibody against NRXN1 alpha in patients with schizophrenia and demonstrated that these antibodies can cause schizophrenia-related pathology in mice. Removal of these antibodies may be a therapeutic target for some patients carrying these antibodies.