Muscarinic receptors downregulation is associated with increased IL6 expression in brain samples of individuals with schizophrenia

Acetylcholine plays a role in the immune system with notable anti-inflammatory properties. Xanomeline, a muscarinic acetylcholine receptor agonist, was recently approved for schizophrenia, marking the first therapy of its kind. Evidence suggests two molecular subtypes of schizophrenia: one characterized by reduced muscarinic receptor expression (muscarinic receptor-deficit schizophrenia, MRDS), and another marked by elevated immune markers, such as Interleukin-6 (IL-6), indicating immune activation. While IL-6 was consistently found to be upregulated in schizophrenia, findings on muscarinic receptor expression have been inconsistent.To explore the relationship between muscarinic receptor genes and IL6 expression, we conducted a systematic meta-analysis of CHRM1-5 and IL6 in postmortem brain samples of patients with schizophrenia. Following PRISMA guidelines, seven independent datasets met our inclusion criteria, comprising 295 samples (151 schizophrenia,144 controls). Our analysis revealed overall CHRM1-5 genes downregulation, with significant downregulation of CHRM1 and CHRM2, alongside upregulation of IL6. Notably, CHRM1 expression showed significant negative correlations with IL6 and its receptors, suggesting an overlap between MRDS and the immune-activated schizophrenia subgroup. This subgroup may benefit from personalized therapies, including Xanomeline or immune system modulators. Further research is required to confirm these findings and investigate targeted treatments.