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

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 EGFα, EGFβ, 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.

Serum Epidermal Growth Factor is Low in Schizophrenia and Not Affected by Antipsychotics Alone or Combined With Electroconvulsive Therapy

“…Compared to the healthy control group, serum EGF was significantly lower in patients prior to drug or combined drug + ECT treatment, in agreement with several previous reports of lower serum EGF in both acute and chronic schizophrenia patients (21,24). EGF regulates cell growth, proliferation, and differentiation through binding to high-affinity EGFRs (1,4,9). Accumulating evidence suggests that neurotrophic factors and cytokines mutually interact to influence neurogenesis and transmitter release, both of which are disrupted in schizophrenia.…”

“…The cytokine epidermal growth factor (EGF) has been proposed as an important effector molecule in schizophrenia (1)(2)(3). Dysregulation of dopaminergic signaling is implicated in the expression of schizophrenic symptoms, and it is well documented that EGF signaling regulates dopaminergic neuron activity and monoamine metabolism in the brain (2,(4)(5)(6)(7)(8)(9).…”

Differential Methylation Pattern of Schizophrenia Candidate Genes in Tetrahydrocannabinol-Consuming Treatment-Resistant Schizophrenic Patients Compared to Non-Consumer Patients and Healthy Controls

“…NRG1 methylation rates did not show any significant group differences although earlier studies revealed higher expression levels of NRG1 in treatment-resistant schizophrenia [48] and clozapine-treated schizophrenic patients [49]. Therefore, it might be concluded that higher expression of NRG1 is not regulated via the alteration of methylation rates.…”

Decreased Serum EGF in First-episode and Chronic Schizophrenia Patients: Negative Correlation with Psychopathology

“…Recently, Haring et al 20 reported that serum levels of EGF were increased in FEP patients, but after for approximately 7 months antipsychotic medication treatment, EGF levels decrease and are related to the clinical improvement of FEP patients. It is well known that EGF protects dopaminergic neurons from glutamate toxicity in culture 6,16,29,30 . Serum EGF levels in patients were lower or higher than in the control group during all the stages of the illness, suggesting that dopaminergic neurons, in the case of patients, were obviously abnormal, and this abnormality is implicated in the mental symptoms and pathogenesis of schizophrenia.…”