Abstract
Currently, the clinical diagnosis of schizophrenia relies solely on self-reporting and clinical interview, and likelycomprises heterogeneous biological subsets. Such subsets may be defined by an underlying biology leading to solidbiomarkers. A transgenic rat model modestly overexpressing the full-length, non-mutantDisrupted-in-Schizophrenia 1 (DISC1) protein (tgDISC1 rat) was generated that defines such a subset, inspired by ourprevious identification of insoluble DISC1 protein inpost mortembrains from patients with chronic mental illness.Besides specific phenotypes such as DISC1 protein pathology, abnormal dopamine homeostasis, and changes inneuroanatomy and behavior, this animal model also shows subtle disturbances in overarching signaling pathwaysrelevant for schizophrenia. In a reverse-translational approach, assuming that both the animal model and a patientsubset share common disturbed signaling pathways, we identified differentially expressed transcripts from peripheralblood mononuclear cells of tgDISC1 rats that revealed an interconnected set of dysregulated genes, led by decreasedexpression of regulator of G-protein signaling 1 (RGS1), chemokine (C–C) ligand 4 (CCL4), and other immune-relatedtranscripts enriched in T-cell and macrophage signaling and converging in one module after weighted genecorrelation network analysis. Testing expression of this gene network in two independent cohorts of patients withschizophrenia versus healthy controls (n=16/50 andn=54/45) demonstrated similar expression changes. The twotop markers RGS1 and CCL4 defined a subset of 27% of patients with 97% specificity. Thus, analogous aberrantsignaling pathways can be identified by a blood test in an animal model and a corresponding schizophrenia patientsubset, suggesting that in this animal model tailored pharmacotherapies for this patient subset could be achieved.
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