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Title: | Peripheral transcription of NRG-ErbB pathway genes are upregulated in treatment-resistant schizophrenia. | Authors: | Pantelis C.;Sundram S. ;Weickert C.S.;Everall I.;Bousman C.;Mostaid M.S.;Lee T.T.;Chana G. | Institution: | (Mostaid, Pantelis, Everall, Bousman) Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Parkville, VIC, Australia (Mostaid, Pantelis, Everall, Bousman) The Cooperative Research Centre (CRC) for Mental Health, Melbourne, VIC, Australia (Lee, Chana, Pantelis, Everall) Centre for Neural Engineering, The University of Melbourne, Carlton, VIC, Australia (Chana, Sundram, Pantelis, Everall) Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia (Chana) Department of Medicine, Royal Melbourne Hospital, Parkville, VIC, Australia (Sundram, Pantelis, Everall) NorthWestern Mental Health, Melbourne, VIC, Australia (Sundram) Department of Psychiatry, School of Clinical Sciences, Monash University and Monash Health, Clayton, VIC, Australia (Weickert) Schizophrenia Research Institute, Sydney, NSW, Australia (Weickert) Schizophrenia Research Laboratory, Neuroscience Research Australia, Sydney, NSW, Australia (Weickert) Faculty of Medicine, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia (Everall) Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom (Bousman) Department of Medical Genetics, University of Calgary, Calgary, AB, Canada (Bousman) Department of Psychiatry, University of Calgary, Calgary, AB, Canada (Bousman) Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada | Issue Date: | 21-Nov-2017 | Copyright year: | 2017 | Publisher: | Frontiers Media S.A. (E-mail: info@frontiersin.org) | Place of publication: | Switzerland | Publication information: | Frontiers in Psychiatry. 8 (NOV) (no pagination), 2017. Article Number: 225. Date of Publication: 06 Nov 2017. | Journal: | Frontiers in Psychiatry | Abstract: | Investigation of peripheral gene expression patterns of transcripts within the NRG-ErbB signaling pathway, other than neuregulin-1 (NRG1), among patients with schizophrenia and more specifically treatment-resistant schizophrenia (TRS) is limited. The present study built on our previous work demonstrating elevated levels of NRG1 EGFalpha, EGFbeta, and type I(Ig2) containing transcripts in TRS by investigating 11 NRG-ErbB signaling pathway mRNA transcripts (NRG2, ErbB1, ErbB2, ErbB3, ErbB4, PIK3CD, PIK3R3, AKT1, mTOR, P70S6K, eIF4EBP1) in whole blood of TRS patients (N = 71) and healthy controls (N = 57). We also examined the effect of clozapine exposure on transcript levels using cultured peripheral blood mononuclear cells (PBMCs) from 15 healthy individuals. Five transcripts (ErbB3, PIK3CD, AKT1, P70S6K, eIF4EBP1) were significantly elevated in TRS patients compared to healthy controls but only expression of P70S6K (Pcorrected = 0.018), a protein kinase linked to protein synthesis, cell growth, and cell proliferation, survived correction for multiple testing using the Benjamini-Hochberg method. Investigation of clinical factors revealed that ErbB2, PIK3CD, PIK3R3, AKT1, mTOR, and P70S6K expression were negatively correlated with duration of illness. However, no transcript was associated with chlorpromazine equivalent dose or clozapine plasma levels, the latter supported by our in vitro PBMC clozapine exposure experiment. Taken together with previously published NRG1 results, our findings suggest an overall upregulation of transcripts within the NRG-ErbB signaling pathway among individuals with schizophrenia some of which attenuate over duration of illness. Follow-up studies are needed to determine if the observed peripheral upregulation of transcripts within the NRG-ErbB signaling pathway are specific to TRS or are a general blood-based marker of schizophrenia.Copyright © 2017 Mostaid, Lee, Chana, Sundram,Shannon Weickert, Pantelis, Everall and Bousman. | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.3389/fpsyt.2017.00225 | Link to associated publication: | Click here for full text options | ISSN: | 1664-0640 (electronic) | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/38759 | Type: | Article | Subjects: | controlled study disease duration disease severity drug blood level female gene *gene expression genetic transcription human human cell in vitro study major clinical study male onset age peripheral blood mononuclear cell *signal transduction *treatment-resistant schizophrenia/dt [Drug Therapy] aged *upregulation chlorpromazine/dt [Drug Therapy] clozapine/cr [Drug Concentration] clozapine/dt [Drug Therapy] *epidermal growth factor receptor/ec [Endogenous Compound] epidermal growth factor receptor 2/ec [Endogenous Compound] epidermal growth factor receptor 3/ec [Endogenous Compound] epidermal growth factor receptor 4/ec [Endogenous Compound] mammalian target of rapamycin/ec [Endogenous Compound] messenger RNA/ec [Endogenous Compound] *neu differentiation factor/ec [Endogenous Compound] S6 kinase/ec [Endogenous Compound] AKT1 gene eIF4EBP gene ERBB1 gene ERBB2 gene ERBB3 gene ERBB4 gene mTOR gene *NRG ErbB signaling pathway NRG2 gene P70S6K gene PIK3CD gene PIK3R3 gene treatment-resistant schizophrenia/dt [Drug Therapy] article adult genetic transcription human human cell in vitro study major clinical study male onset age peripheral blood mononuclear cell *signal transduction *treatment-resistant schizophrenia / *drug therapy treatment-resistant schizophrenia / drug therapy *upregulation adult aged controlled study disease duration disease severity drug blood level female gene *gene expression Article |
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