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Neuregulin1-induced cell migration is impaired in schizophrenia: Association with neuregulin1 and catechol-o-methyltransferase gene polymorphisms

Clinical Brain Disorder Branch, Genes, Cognition, and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1385, USA.
Molecular Psychiatry (Impact Factor: 14.5). 11/2007; 12(10):946-57. DOI: 10.1038/sj.mp.4001994
Source: PubMed

ABSTRACT

Neuregulin1 (NRG1), a candidate susceptibility gene for schizophrenia, plays a critical role in neuronal migration and central nervous system development. However, its relation to schizophrenia pathogenesis is unknown. Here we show that B lymphoblasts migrate to NRG1 through the ErbB-signaling system as observed in neuronal cells. We assessed NRG1-induced cell migration in B lymphoblasts from patients with schizophrenia and found that NRG1-induced migration is significantly decreased compared with control individuals in two independent cohorts. This impaired migration is related at least in part to reduced AKT phosphorylation in the patients. Moreover, the magnitude of NRG1-induced migration is associated with polymorphisms of the NRG1 and catechol-o-methyltransferase genes and with an epistatic interaction of these genes. This study demonstrates that the migratory response of schizophrenia-derived cells to NRG1 is impaired and is associated with genetic variations in more than one schizophrenia susceptibility gene, providing a novel insight into potential neurodevelopmental mechanisms of schizophrenia.

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    • "Animals with heterozygous disruption of Nrg1 or ErbB4 receptor functions are hyperactive with PPI deficits and have altered social behavior, consistent with those findings in patients with schizophrenia (Chen et al., 2008; Hong et al., 2008). Furthermore, psychopharmacological and animal model studies linked dysregulation of Akt/mTOR signaling pathway with major mental and mood disorders (Emamian et al., 2004; Sei et al., 2007). Both AKT1 and AKT2 express Figure 9 The effect of clozapine and sarcosine on percent PPI of ASR. "
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    ABSTRACT: Glycine N-methyltransferase (GNMT) affects cellular methylation capacity through regulating the ratio between S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH). The product of its enzymatic reaction-sarcosine has antipsychotic effect in patients with schizophrenia. In this study, through RT-PCR and immunohistochemical staining, we demonstrated that GNMT expressed in various neurons located in the cerebral cortex, hippocampus, substantia nigra and cerebellum. Compared to the wild-type mice, Gnmt-/- mice had significantly lower level of sarcosine in the cerebral cortex. Real-time PCR identified genes involved in the methionine metabolism (Dnmt1 and Dnmt3a), ErbB (Nrg1 and ErbB4) and mTOR (Akt2, S6, S6k1 and S6k2) signaling pathways were dysregulated significantly in the cortex of Gnmt-/- mice. Acoustic startle reflex test demonstrated that Gnmt-/- mice had significantly lower level of prepulse inhibition and the deficit was ameliorated through clozapine or sarcosine treatment. Furthermore, liver-specific-human-GNMT transgenic with Gnmt-/- (Tg-GNMT/Gnmt-/-) mice were used to rule out that the phenotype was due to abnormal liver function. In summary, the neuropsychological abnormalities found in Gnmt-/- mice may represent an endophenotype of schizophrenia. GNMT plays an important role in maintaining normal physiological function of brain and Tg-GNMT/Gnmt-/- mice are useful models for development of therapeutics for patients with schizophrenia.
    Full-text · Article · Jan 2012 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
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    • "We used standard methods reported previously (Sei et al., 2007Sei et al., , 2010 Kéri et al., 2009, 2010, 2011 ). B lymphocytes in the mononuclear cell preparation were transformed by EpsteineBarr virus. "
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    ABSTRACT: The phosphoinositide 3'-kinase (PI3K)--protein kinase B (AKT1)--glycogen synthase kinase (GSK)-3β system is modulated by several factors implicated in the pathophysiology of schizophrenia. Evidence suggests that neuregulin 1 (NRG1) induces decreased AKT phosphorylation in schizophrenia relative to healthy controls, which may be related to dysfunctional neurodevelopment and neuroplasticity. The aim of this study was to investigate the relationship between NRG1--induced AKT phosphorylation and hippocampal volume in schizophrenia. Participants were 20 first-episode patients with schizophrenia who did not receive psychotropic medications and 20 matched healthy controls. We measured the phosphorylated AKT--total AKT and phosphorylated ERK (extracellular signal-regulated kinase)--total ERK ratios in peripheral lymphoblasts before and after NRG1 administration. Whole-brain, left, and right hippocampal volumes were quantified using FreeSurfer software. Patients with schizophrenia displayed decreased AKT but normal ERK ratio compared with controls. Patients also had a reduction in left hippocampal volume. There was no significant difference between patients and controls in whole-brain and right hippocampal volume. Decreased AKT ratio was associated with reduced hippocampal volume. There was no significant relationship between ERK ratio and brain structure. Activation of the AKT system is specifically associated with hippocampal volume in first-episode schizophrenia, which provides further evidence for the pivotal role of this messenger system in the pathophysiology of psychotic disorders.
    Full-text · Article · Dec 2011 · Journal of Psychiatric Research
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    • "Intracellular signaling pathways which have been demonstrated to be subsequently activated include the extracelullar signal regulated kinases (ERK), the p38 mitogenactivated protein kinases (p38 MAPK), and the phospha- tidylinositol-3-kinase (PI3K)/Akt pathway. These can modulate distinct aspects of the cellular response for instance ERK signaling promotes cell proliferation and PI3K/Akt cellular motility (Eckert et al., 2009; Maurel and Salzer, 2000; Sei et al., 2007) in response to NRG1. "
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    ABSTRACT: Following peripheral nerve injury microglia accumulate within the spinal cord and adopt a proinflammatory phenotype a process which contributes to the development of neuropathic pain. We have recently shown that neuregulin-1, a growth factor released following nerve injury, activates erbB 2, 3, and 4 receptors on microglia and stimulates proliferation, survival and chemotaxis of these cells. Here we studied the intracellular signaling pathways downstream of neuregulin-1-erbB activation in microglial cells. We found that neuregulin-1 in vitro induced phosphorylation of ERK1/2 and Akt without activating p38MAPK. Using specific kinase inhibitors we found that the mitogenic effect of neuregulin-1 on microglia was dependant on MEK/ERK1/2 pathway, the chemotactic effect was dependant on PI3K/Akt signaling and survival was dependant on both pathways. Intrathecal treatment with neuregulin-1 was associated with microgliosis and development of mechanical and cold pain related hypersensitivity which was dependant on ERK1/2 phosphorylation in microglia. Spinal nerve ligation results in a robust microgliosis and sustained ERK1/2 phosphorylation within these cells. This pathway is downstream of neuregulin-1/erbB signaling since its blockade resulted in a significant reduction in microglial ERK1/2 phosphorylation. Inhibition of the MEK/ERK1/2 pathway resulted in decreased spinal microgliosis and in reduced mechanical and cold hypersensitivity after peripheral nerve damage. We conclude that neuregulin-1 released after nerve injury activates microglial erbB receptors which consequently stimulates the MEK/ERK1/2 pathway that drives microglial proliferation and contributes to the development of neuropathic pain.
    Full-text · Article · Apr 2011 · Glia
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