AUTHOR=Mostaid Md Shaki , Lee Ting Ting , Chana Gursharan , Sundram Suresh , Shannon Weickert Cynthia , Pantelis Christos , Everall Ian , Bousman Chad 

TITLE=Peripheral Transcription of NRG-ErbB Pathway Genes Are Upregulated in Treatment-Resistant Schizophrenia

JOURNAL=Frontiers in Psychiatry

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2017.00225

DOI=10.3389/fpsyt.2017.00225

ISSN=1664-0640

ABSTRACT=<p>Investigation of peripheral gene expression patterns of transcripts within the <italic>NRG–ErbB</italic> signaling pathway, other than neuregulin-1 (<italic>NRG1</italic>), 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 <italic>NRG1</italic> EGFα, EGFβ, and type I<sub>(Ig2)</sub> containing transcripts in TRS by investigating 11 <italic>NRG–ErbB</italic> signaling pathway mRNA transcripts (<italic>NRG2, ErbB1, ErbB2, ErbB3, ErbB4, PIK3CD, PIK3R3, AKT1, mTOR, P70S6K, eIF4EBP1</italic>) in whole blood of TRS patients (<italic>N</italic> = 71) and healthy controls (<italic>N</italic> = 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 (<italic>ErbB3, PIK3CD, AKT1, P70S6K, eIF4EBP1</italic>) were significantly elevated in TRS patients compared to healthy controls but only expression of <italic>P70S6K</italic> (<italic>P</italic><sub>corrected</sub> = 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 <italic>ErbB2, PIK3CD, PIK3R3, AKT1, mTOR</italic>, and <italic>P70S6K</italic> 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 <italic>in vitro</italic> PBMC clozapine exposure experiment. Taken together with previously published <italic>NRG1</italic> results, our findings suggest an overall upregulation of transcripts within the <italic>NRG–ErbB</italic> 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 <italic>NRG–ErbB</italic> signaling pathway are specific to TRS or are a general blood-based marker of schizophrenia.</p>