Summary: A study reveals a connection between schizophrenia and autoimmune reactions. The researchers identified autoantibodies against the synaptic protein neurexin 1α in about 2% of patients with schizophrenia.
These autoantibodies, when injected into mice, blocked synaptic communication and induced schizophrenia-related behaviors. This discovery might provide a new target for therapeutic interventions, especially for patients resistant to current antipsychotic treatments.
Synaptic adhesion proteins, such as neurexin 1α, help to form connections (synapses) between brain cells, allowing communication through molecule exchange.
In the study, about 2% of patients with schizophrenia had autoantibodies against neurexin 1α, which, when injected into mice, induced schizophrenia-like changes and behaviors.
These findings could potentially open up new therapeutic avenues for patients with schizophrenia, especially those who are resistant to current antipsychotic treatments.
Source: Tokyo Medical and Dental University
Links have been reported between schizophrenia and proteins produced by the immune system that can act against one’s own body, known as autoantibodies.
In a study published last month in Brain Behavior and Immunity, Japanese researchers identified autoantibodies that target a ‘synaptic adhesion protein’, neurexin 1α, in a subset of patients with schizophrenia.
When injected into mice, the autoantibodies caused many schizophrenia-related changes.
What is a synaptic protein, and why might it be linked to schizophrenia? Synaptic adhesion proteins are specialized proteins that bind to create physical connections between brain cells. These connections, called synapses, allow the cells to communicate by passing molecules back and forth.
Both synapses and autoimmunity are known to be associated with schizophrenia, so the research team from Tokyo Medical and Dental University (TMDU) decided to investigate autoantibodies that target synaptic proteins in patients with schizophrenia.
“In around 2% of our patient population, we identified autoantibodies against the synaptic protein neurexin 1α, which is expressed by one cell in the synapse and binds to proteins known as neuroligins on the other cell in the synapse,” says lead author of the study Hiroki Shiwaku.
“Once we had identified these autoantibodies, we wanted to see if they were able to cause schizophrenia-related changes.”
To do this, the researchers isolated autoantibodies from some of the patients with schizophrenia and injected them into the cerebrospinal fluid of mice, so that the autoantibodies would travel into the brain. In these mice, the autoantibodies blocked neurexin 1α and neuroligin binding and altered some related synaptic properties.
The administration of these autoantibodies also resulted in fewer synapses in the brains of mice and schizophrenia-related behaviors, such as reduced social behavior toward unfamiliar mice and reduced cognitive function.
“Together, our results strongly suggest that autoantibodies against neurexin 1α can cause schizophrenia-related changes, at least in mice,” explains Hiroki Shiwaku. “These autoantibodies may therefore represent a therapeutic target for a subset of patients with schizophrenia.”
Schizophrenia has a wide variety of both symptoms and treatment responses, and many patients have symptoms that are resistant to currently available treatment options. Therefore, the identification of possible disease-causing autoantibodies is important for improving symptom control in patients with schizophrenia.
It is hoped that the results of this investigation will allow patients with autoantibodies that target neurexin 1α—all of whom were resistant to antipsychotic treatment in the present study—to better control their symptoms in the future.
Analyzing schizophrenia-related phenotypes in mice caused by autoantibodies against NRXN1α 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 1α (NRXN1α), 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 NRXN1α 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-NRXN1α autoantibodies.
Anti-NRXN1α autoantibodies isolated from patients with schizophrenia inhibited the molecular interaction between NRXN1α and Neuroligin 1 (NLGN1) and between NRXN1α 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-NRXN1α 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-NRXN1α autoantibodies from the IgG fraction of patients with schizophrenia.
These findings demonstrate that anti-NRXN1α autoantibodies transferred from patients with schizophrenia cause schizophrenia-related pathology in mice. Removal of anti-NRXN1α autoantibodies may be a therapeutic target for a subgroup of patients who are positive for these autoantibodies.