Neuregulin 1–erbB4 pathway in schizophrenia: From genes to an interactome

Banerjee, Anamika; MacDonald, Mathew L.; Borgmann‐Winter, Karin; Hahn, Chang-Gyu

doi:10.1016/j.brainresbull.2010.04.011

Cited by 70 publications

(66 citation statements)

References 116 publications

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“…Studies have found that levels of NRG1 and ErbB4 were up-regulated in the hippocampus. These differences may be partly due to degrees of alteration in risk genes [48], or partly due to the duration of the modification on NRG1 signaling [23]. In addition, specificity of antibodies against specific NRG1 and ErbB4 may also contribute to differences.…”

Section: Discussionmentioning

confidence: 99%

Sub-chronic Antipsychotic Drug Administration Reverses the Expression of Neuregulin 1 and ErbB4 in a Cultured MK801-Induced Mouse Primary Hippocampal Neuron or a Neurodevelopmental Schizophrenia Model

Tang

Yang

et al. 2016

Neurochem Res

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It has been reported that specific environmental influences during the postpartum period might contribute to the development of schizophrenia (SZ). Administration of MK801 during early development led to persistent brain pathology. Glutamate decarboxylase 1 (GAD67) and parvalbumin (PV), and neuregulin 1 (NRG1)/ErbB4 signaling were closely associated with SZ pathology. We postulated therefore that NMDA receptor antagonists exposure during the postpartum period may be associated with expression dysregulation of some of the SZ candidate proteins. To test this, we used mouse primary hippocampal neurons and neonatal male mice treated with the NMDA receptor antagonist, MK801 at postnatal day 4 (P4) or P7, followed by the treatments of antipsychotic drugs (i.e., olanzapine, risperidone, and haloperidol). The expressions of GAD67, PV, NRG1, and ErbB4 in in vitro and in vivo SZ models were detected with Western blot analysis and immunohistochemistry, respectively. Behavioral tests (locomotion activity, social interaction, novel object recognition and prepulse inhibition) were measured. We found MK801 decreased the expression of GAD67, PV, NRG1 and ErbB4, and induced obvious behavioral alterations, while antipsychotics reversed these alterations. These results suggest that exposure to the NMDA receptor antagonist in early development may lead to long-lasting influence on the expression of specific proteins, such as GAD67, PV, NRG1, and ErbB4. Moreover, our results suggest that rescue of the activation of the NRG1/ErbB4 signaling pathway may be one of the mechanisms by which antipsychotic drugs have an antipsychotic effect.

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Section: Discussionmentioning

confidence: 99%

Sub-chronic Antipsychotic Drug Administration Reverses the Expression of Neuregulin 1 and ErbB4 in a Cultured MK801-Induced Mouse Primary Hippocampal Neuron or a Neurodevelopmental Schizophrenia Model

Tang

Yang

et al. 2016

Neurochem Res

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“…These differences are partly due to the fact that patients' risk genotypes have only some subtle variations, while transgenic mice have a pronounced gene alteration (Banerjee et al, 2010), or partly due to the duration of the modification of NRG1 signalling (Savonenko et al, 2008). Furthermore, dysregulated NRG1-ErbB4 signalling in schizophrenia might interact with other signalling pathways such as glutamatergic, GABAergic and dopaminergic pathways (Banerjee et al, 2010;Buonanno, 2010). It is important that antipsychotic drugs are able to reverse some abnormal behaviours in NRG1 and ErbB4 mutant mice, and affect the expression of Hashimoto et al, 2004 (1) NRG1 type I expression increased in the PFC of schizophrenia patients.…”

Section: Discussionmentioning

confidence: 99%

Antipsychotic treatment and neuregulin 1–ErbB4 signalling in schizophrenia

Pan

Huang

Deng

2011

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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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).

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“…We also studied FOXP2 interactions using STRING [36,37] (Figure 3a), BioGRID [38] and IntAct [64]. For a more extensive study, we referred scientific literature [60][61][62][63][64][65][66][67][68][69] and took into consideration some genes that were not common targets but play important roles in the nervous system or in pathogenesis of neurological disorders (for example, CNTNAP2 and BDNF) and showed potential in being indirectly co-regulated by FOXP2 and miR-3666 through common target genes. Therefore, a total of 30 genes were selected for developing our models (Supplementary Table S4).…”

Section: Four Models Developed Show Mechanisms By Which Mir-3666 Mighmentioning

confidence: 99%

“…As model 3 (Figure 5c) shows, the candidate gene ERBB4 [87], being a common target gene, may be directly regulated by miR-3666 and FOXP2. However, miR-3666 and FOXP2 can regulate the levels of candidate genes BDNF (Brain-Derived Neurotrophic Factor) [88], DGCR2 (DiGeorge syndrome critical region gene 2) [89], NRG1 [60] through common target CREB1. This relation is evident from the GEO2R analysis of GSE17612 [90] expression data where upregulation of FOXP2 The left circle represents disease candidate genes, where the number in the blue circle corresponds to genes exclusive for the disease.…”

Section: Foxp2 and Mir-3666 May Be Responsible For The Pathogenesis Omentioning

confidence: 99%

Intronic miRNA miR-3666 Modulates its Host Gene FOXP2 Functions in Neurodevelopment and May Contribute to Pathogenesis of Neurological Disorders Schizophrenia and Autism

Islam¹

2017

JABB

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MicroRNAs (miRNAs) are approximately 22-nucleotide-long, non-coding RNAs that bind to complementary mRNAs with inhibitory effect. An intronic miRNA is embedded in a particular gene called its host gene. Our study focuses on the Homo sapiens intronic miRNA-host gene pair, hsa-miR-3666 and FOXP2. Previous report of coexpression of miR-3666 and FOXP2 indicates possible regulation of FOXP2 functions by miR-3666. However, direct correlation has not been shown yet. Therefore, we took a computational approach to determine if and how such modulation occurs. ChIP-seq identified FOXP2 targets and putative miR-3666 targets showed a significant overlap of 574 common target genes. Functional enrichment analysis of common targets revealed over-representation of KEGG pathways and Gene Ontology modules associated with neurodevelopment. These modules, along with further literature mining and proteinprotein interaction analysis of FOXP2 and miR-3666 identified several specific genes associated with neurodevelopment and finally integration of transcriptomic expressions data lead to the selection of four models depicting the mechanisms by which miR-3666 can modulate FOXP2 functions. Model 1 illustrates that during neurodevelopment, miR-3666 can directly modulate the functions of FOXP2 through regulation of common targets, such as IGF1 and EFNB2, whereas model 2 shows miR-3666 can also indirectly modulate FOXP2 functions by considering targets that are not common for the intronic miRNA-host gene pair, for example CDH2 and LMO4. This direct and indirect regulation is necessary for precise spatial and temporal expression of genes during neurodevelopment. Models 3 and 4 exhibit mechanisms in which the interactions of miR-3666 and FOXP2 with target genes contribute to the pathogenesis of schizophrenia and autism respectively. a role in transcriptional activation [7]. FOXP2 hosts the intronic miRNA, miR-3666. Though not much work has been done on miR-3666, its targets have been predicted and deposited in various databases. A few recent experiments have shown the repression activity of miR-3666 on targets such as MET and ZEB1 in thyroid carcinoma and cervical carcinoma cells, respectively [9,10].

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Neuregulin 1–erbB4 pathway in schizophrenia: From genes to an interactome

Cited by 70 publications

References 116 publications

Sub-chronic Antipsychotic Drug Administration Reverses the Expression of Neuregulin 1 and ErbB4 in a Cultured MK801-Induced Mouse Primary Hippocampal Neuron or a Neurodevelopmental Schizophrenia Model

Sub-chronic Antipsychotic Drug Administration Reverses the Expression of Neuregulin 1 and ErbB4 in a Cultured MK801-Induced Mouse Primary Hippocampal Neuron or a Neurodevelopmental Schizophrenia Model

Antipsychotic treatment and neuregulin 1–ErbB4 signalling in schizophrenia

Intronic miRNA miR-3666 Modulates its Host Gene FOXP2 Functions in Neurodevelopment and May Contribute to Pathogenesis of Neurological Disorders Schizophrenia and Autism

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