Dysregulation of the synaptic sheddome in schizophrenia

Schizophrenia is a debilitating mental disorder that affects millions of people worldwide. Large-scale genomics studies have recently identified over 100 genes that contribute to schizophrenia risk. Remarkably, may of these genes encode synaptic proteins. However, genetic studies do not provide direct insight into the pathophysiological processes that undelie the clnical manifestations of the disease. We have recently shown that many transmembrane synaptic proteins undergo ectodomain shedding, a process through which the extracellular domain of proteins is cleaved by proteases and released into the brain millieu. We also showed that the abundance of one synaptic ectodomain is altered in the cerebrospinal fluid of patients with autism. We thus hypothesized that analysis of the "synaptic sheddome", or the set of shed synaptic proteins in the cerebrospinal fluid of patients could provide insight into pathophysiology of specific mental disorders. To test this hypothesis and to gain insight into pathophysiological processes in schizophrenia, we used cutting-edge proteomics methods. We analyzed cerebrospinal fluid from patients with schizophrenia and compared them to healthy controls using tandem mass-tag spectrometry. We identified several downregulated proteins, and computationally defined the subset which underwent ectodomain shedding. Among these were several synaptic proteins and ion channels not yet known to undergo ectodomain shedding. The ectodomains of several calcium channel subunits were less abundant in the cerebrospinal fluid of schizophrena patients versus controls. We then investigated the functions of one these ectodomains, and found that it acted as an intercellular signaling molecule, and modulated neuronal structure and function, as well as circuit properties. Our finings support several impactful conclusions: 1) synaptic ectodomain shedding is altered in mental disorders; 2) these alterations can be detected in the cerebrospinal fluid, reflecting biochemical changes in patient's brains; 3) such altered synaptic ectodomains control disease-relevant neurobiological processes and thus contribute to pathophysiology. None