Brain inflammation generally accompanies and accelerates neurodegeneration. Here we report a microglial mechanism in which polyglutamine binding protein 1 (PQBP1) senses extrinsic tau 3R/4R proteins by direct interaction and triggers an innate immune response by activating a cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) pathway. Tamoxifen-inducible and microglia-specific depletion of PQBP1 in primary culture in vitro and mouse brain in vivo shows that PQBP1 is essential for sensing-tau to induce nuclear translocation of nuclear factor κB (NFκB), NFκB-dependent transcription of inflammation genes, brain inflammation in vivo, and eventually mouse cognitive impairment. Collectively, PQBP1 is an intracellular receptor in the cGAS-STING pathway not only for cDNA of human immunodeficiency virus (HIV) but also for the transmissible neurodegenerative disease protein tau. This study characterises a mechanism of brain inflammation that is common to virus infection and neurodegenerative disorders.

From genetic and etiological studies, autoimmune mechanisms underlying schizophrenia are suspected; however, the details remain unclear. In this study, we describe autoantibodies against neural cell adhesion molecule (NCAM1) in patients with schizophrenia (5.4%, cell-based assay; 6.7%, ELISA) in a Japanese cohort (n = 223). Anti-NCAM1 autoantibody disrupts both NCAM1-NCAM1 and NCAM1-glial cell line-derived neurotrophic factor (GDNF) interactions. Furthermore, the anti-NCAM1 antibody purified from patients with schizophrenia interrupts NCAM1-Fyn interaction and inhibits phosphorylation of FAK, MEK1, and ERK1 when introduced into the cerebrospinal fluid of mice and also reduces the number of spines and synapses in frontal cortex. In addition, it induces schizophrenia-related behavior in mice, including deficient pre-pulse inhibition and cognitive impairment. In conclusion, anti-NCAM1 autoantibodies in patients with schizophrenia cause schizophrenia-related behavior and changes in synapses in mice. These antibodies may be a potential therapeutic target and serve as a biomarker to distinguish a small but treatable subgroup in heterogeneous patients with 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.

The potential role of autoantibodies in the etiology of schizophrenia is a key research focus because growing evidence suggests an association between immune dysfunction and psychotic disorders. This hypothesis is supported by findings indicating immune‐related abnormalities in patients with schizophrenia, including chronic inflammation and genetic alterations associated with immune system dysregulation. Epidemiological studies have reinforced this perspective by demonstrating a significant correlation between autoimmune diseases and schizophrenia, suggesting shared pathological mechanisms including autoantibodies. A particularly compelling line of evidence comes from the identification of autoantibodies targeting synaptic molecules in patients with schizophrenia. Autoantibodies against N‐methyl‐D‐aspartate (NMDA) receptors, gamma‐aminobutyric acid (GABA) receptors, neural cell adhesion molecule 1 (NCAM1), and neurexin 1 (NRXN1) have been detected in patients, raising the possibility that immune‐mediated synaptic dysfunction contributes to the disorder's pathophysiology. Experimental studies support this notion because the administration of these autoantibodies in mice induces molecular, cellular, and behavioral abnormalities that mirror aspects of schizophrenia. This review summarizes the relationships among schizophrenia, inflammation, immune‐related genetic factors, autoimmune diseases, and autoantibodies. Furthermore, this review discusses future research directions for further elucidating the role of autoantibodies in schizophrenia.

The long-term use of benzodiazepines is not recommended for the treatment of major depressive disorder (MDD) due to the risk of adverse effects, including dependence, falls, dementia, mortality and the lack of evidence of effectiveness for symptoms other than anxiety. However, there are many patients with MDD for whom antidepressants are co-administrated with benzodiazepines. This study aimed to identify whether the use of benzodiazepines is associated with a lower risk of relapse or recurrence of MDD in some patients, and the characteristics of these patients. Kaplan–Meier survival analysis was used to quantify the relapse and recurrence of MDD in 108 patients with MDD who achieved remission during hospitalization. Among them, 26 patients had been diagnosed with severe MDD with psychotic features. There was no significant difference in the rate of relapse/recurrence between patients with and without benzodiazepines when all patients were analyzed together. However, among the 26 patients with psychotic depression, 21.2% in the benzodiazepine group and 75.0% in the non-benzodiazepine group experienced relapse (log rank p = 0.0040). Kaplan–Meier survival analysis revealed that this effect was dose-dependent. The adjunctive use of benzodiazepines may reduce relapse/recurrence rates in patients with severe MDD with psychotic features.