ELEVATED PERIPHERAL EXPRESSION OF NEUREGULIN-1 (NRG1) MRNA ISOFORMS IN PATIENTS WITH TREATMENT-RESISTANT SCHIZOPHRENIA

Background Differential expression of Neuregulin-1 (NRG1) mRNA isoforms and proteins has been reported in schizophrenia, primarily in post-mortem brain tissue. In this study, we examined 12 NRG1 SNPs, eight NRG1 mRNA isoforms (type I, type I(Ig2), type II, type III, type IV, EGFα, EGFβ, pan-NRG1) in whole blood, and NRG1-β1 protein in serum of clozapine-treated schizophrenia patients (N=71) and healthy controls (N=57). In addition, using cultured Peripheral Blood Mononuclear Cells (PBMC) from 15 healthy individuals, we examined the effect of clozapine on NRG1 mRNA isoform and protein expression. Methods RT-PCR was used to measure gene expression level of different NRG1 isoforms in the whole blood of the schizophrenia patients and healthy controls in the clinical cohort as well as from the total RNA extracted from the In-Vitro clozapine exposure study. ELISA was used to measure NRG1-β1 protein level in serum in the clinical cohort and also in the total protein extracted from the in vitro clozapine exposure study. Results We found elevated levels of NRG1 mRNA, specifically the EGFα (P=0.0175), EGFβ (P=0.002) and typeI(Ig2) (P=0.023) containing transcripts, but lower NRG1-β1 serum protein levels (p=0.019) in schizophrenia patients compared to healthy controls. However, adjusting for smoking status attenuated the difference in NRG1-β1 serum levels (p=0.050). Examination of clinical factors showed NRG1 EGFα (p=0.02) and EGFβ (p=0.02) isoform expression was negatively correlated with age of onset. However, we found limited evidence that NRG1 mRNA isoform or protein expression was associated with current chlorpromazine equivalent dose or clozapine plasma levels, the latter corroborated by our PBMC clozapine exposure experiment. Our SNP analysis found no robust expression quantitative trait loci. Discussion Our results represent the first comprehensive investigation of NRG1 isoforms and protein expression in the blood of clozapine-treated schizophrenia patients and suggest NRG1 transcription is up-regulated in those with schizophrenia and perhaps more specifically in treatment-resistant schizophrenia.