Antipsychotic treatment and neuregulin 1–ErbB4 signalling in schizophrenia

Abstract

Evidence from genetic, transgenic and post-mortem studies has strongly supported the critical role that neuregulin 1 (NRG1) and its ErbB4 receptor plays in the pathophysiology of schizophrenia. This article aims to review current evidence regarding the effects of antipsychotic treatment on NRG1-ErbB4 signalling. NRG1 and ErbB4 knockout mice display abnormal behaviours relevant to certain features of schizophrenia, which could be improved by antipsychotic (clozapine/haloperidol) treatment. In contrast to most NRG1/ ErbB4 knockout mice with a decreased NRG1-ErbB4 signalling, the majority post-mortem studies showed an increased NRG1-ErbB4 signalling in schizophrenic patients. These differences could be due to degrees of alteration in risk genes (subtle variations in patients vs pronounced alteration in mutant mice) or the duration of the modification on NRG1 signalling. Various antipsychotics have different effects on NRG1 and ErbB4 expression and signalling that are dependent on treatment duration. Current evidence suggests that a chronic (12 weeks) antipsychotic treatment, at least in animal models, could downregulate NRG1-ErbB4 signalling, although an upregulation is seen for a short-term treatment. These effects may be due to multiple binding profiles with various G-coupled protein receptors (e.g. dopamine, and serotonin receptors) of antipsychotics. Studies are needed to investigate the interactions between NRG1-ErbB4 and the other signalling pathways (such as glutamatergic, GABAergic and dopaminergic). Furthermore, the interactions between NRG1/ErbB4 and other schizophrenia suspensibility genes under antipsychotic treatment also require investigation. and ErbB4 knockout mice display some schizophrenia-like behavioural abnormalities, which could be improved by antipsychotic (clozapine/haloperidol) treatment. In contrast to NRG1/ErbB4 knockout mice with a decreased NRG1-ErbB4 signalling, the majority post-mortem studies showed an increased NRG1-ErbB4 signalling in schizophrenia patients. These differences could be due to degrees of alteration in risk genes (subtle variations in patients vs pronounced alteration in mutant mice) or the duration of the modification on NRG1 signalling. Various antipsychotics have different effects on NRG1 and ErbB4 expression and signalling dependent on treatment duration. Current evidence suggests that a chronic (12 weeks) antipsychotic treatment, at least in animal models, downregulates NRG1-ErbB4 signalling, although an upregulation is seen for a short term treatment. Therefore, the dysfunctional NRG1-ErbB4 signalling observed in schizophrenia is unlikely to be due to antipsychotic therapy. Furthermore, multiple-receptor binding profiles (e.g. dopamine, and 5-HT receptors) of antipsychotics may also contribute to their different influences on NRG1-ErbB4 signalling. Studies are also needed to investigate the interactions between NRG1-ErbB4 and the other signalling pathways (such as glutamatergic, GABAergic and dopaminergic).

Receptor Tyrosine Kinases in the Nucleus

“…Interestingly, there is a genetic correlation between ErbB-4 and schizophrenia (Pan et al 2011) and the involvement of the ICD fragment in controlling gene expression in relevant cell types has been reported (Wong and Weickert 2009;Allison et al 2011). Also, the maturation of fetal lung cells is reported to be dependent on secretase processing of ErbB-4 and ICD association with the transcription factors YAP (Hoeing et al 2011), STAT 5a (Zscheppang et al 2011a), and ERb (Zscheppang et al 2011b).…”

Neural stem cells: mechanisms and modeling

“…Genome-wide association studies (GWAS) have identified a number of genes involved in SCZD. The expression and functions of three major genes, the Disrupted-in-Schizophrenia-1 (DISC1) gene (Kang et al, 2011;Singh et al, 2011;Soares et al, 2011), the Neuregulin-1 (NRG1) gene and its receptor ErbB4 (Pan et al, 2011;Yokley et al, 2011), have been firmly verified to alter during SCZD. Other genes, including transcription factor 4 (TCF4), zinc finger protein 804A (ZNF804A), neurogranin (NRGN), and microRNA 137 (MIR137) (O'Donovan et al, 2008;Stefansson et al, 2009;Ripke et al, 2011) probably contribute to SCZD.…”

Effects of prolonged antipsychotic administration on neuregulin-1/ErbB signaling in rat prefrontal cortex and myocardium: implications for the therapeutic action and cardiac adverse effect

“…Genetic variations in NRG1/ErbB system have been associated with both SCZ and CVD (HuertasVazquez et al, 2013). Chronic antipsychotic treatment can exert modulatory effects on NRG1/ErbB pathway and improve the behavioral abnormalities relevant to certain features of SCZ in transgenic mice with impaired NRG1/ ErbB signaling (Pan et al, 2011). These findings implicated NRG1/ErbB pathway in the development of SCZ and pharmacological actions of antipsychotics.…”