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Bjarnadottir M, Misner DL, Haverfield-Gross S, Bruun S, Helgason VG, Stefansson H et al. Neuregulin1 (NRG1) signaling through Fyn modulates NMDA receptor phosphorylation: differential synaptic function in NRG1± knock-outs compared with wild-type mice. J Neurosci 27: 4519-4529

deCODE Genetics, 101 Reykjavik, Iceland.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 05/2007; 27(17):4519-29. DOI: 10.1523/JNEUROSCI.4314-06.2007
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ABSTRACT We previously identified Neuregulin1 (NRG1) as a gene contributing to the risk of developing schizophrenia. Furthermore, we showed that NRG1+/- mutant mice display behavioral abnormalities that are reversed by clozapine, an atypical antipsychotic drug used for the treatment of schizophrenia. We now present evidence that ErbB4 (v-erb-a erythroblastic leukemia viral oncogene homolog 4), the tyrosine kinase receptor for NRG1 in hippocampal neurons, interacts with two nonreceptor tyrosine kinases, Fyn and Pyk2 (proline-rich tyrosine kinase 2). NRG1 stimulation of cells expressing ErbB4 and Fyn leads to the association of Fyn with ErbB4 and consequent activation. Furthermore, we show that NRG1 signaling, through activation of Fyn and Pyk2 kinases, stimulates phosphorylation of Y1472 on the NR2B subunit of the NMDA receptor (NMDAR), a key regulatory site that modulates channel properties. NR2B Y1472 is hypophosphorylated in NRG1+/- mutant mice, and this defect can be reversed by clozapine at a dose that reverses their behavioral abnormalities. We also demonstrate that short-term synaptic plasticity is altered and theta-burst long-term potentiation is impaired in NRG1+/- mutant mice, and incubation of hippocampal slices from these mice with NRG1 reversed those effects. Attenuated NRG1 signaling through ErbB4 may contribute to the pathophysiology of schizophrenia through dysfunction of NMDAR modulation. Thus, our data support the glutamate hypothesis of schizophrenia.

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Available from: Gudmundur Vignir Helgason, Sep 19, 2014
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    • "Recent research has identified an involvement of NRG1 signaling in neurotransmission of the adult brain, such as GABA release (Woo et al., 2007; Wen et al., 2010), GABA receptor currents (Woo et al., 2007; Chen et al., 2010), and receptor expression levels (Okada and Corfas, 2004; Allison et al., 2011; Mitchell et al., 2013). Furthermore, glutamate release (Gu et al., 2005; Pitcher et al., 2011; Yin et al., 2013) and N-Methyl- D-aspartic acid (NMDA) receptor functions are also reportedly influenced by NRG1 signaling (Gu et al., 2005; Bjarnadottir et al., 2007; Bennett, 2009; Pitcher et al., 2011). The neurotransmission effects of NRG1 appear to be primarily mediated through the epidermal growth factor receptor tyrosine kinase ERBB4, but might also involve other epidermal growth factor receptor tyrosine kinase (ERBB) receptor isoforms (Iwakura and Nawa, 2013; Mei and Nave, 2014). "
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    ABSTRACT: Background: Substantial evidence from human postmortem and genetic studies have linked the neurotrophic factor neuregulin 1 (NRG1) to the pathophysiology of schizophrenia. Genetic animal models and in vitro experiments have suggested that altered NRG1 signaling, rather than protein changes, contributes to the symptomatology of schizophrenia. However, little is known about the effect of NRG1 on schizophrenia-relevant behavior and neurotransmission (particularly GABAergic and glutamatergic) in adult animals. METHOD: To address this question, we treated adult mice with the extracellular signaling domain of NRG1 and assessed spontaneous locomotor activity and acoustic startle response, as well as extracellular GABA, glutamate and glycine levels in the prefrontal cortex and hippocampus via microdialysis. Furthermore, we asked whether the effect of NRG1 would differ under schizophrenia-relevant impairments in mice and therefore co-treated mice with NRG1 and phencyclidine (3 mg/kg). RESULTS: Acute intraventricularly or systemically injected NRG1 did not affect spontaneous behavior, but prevented PCP-induced hyperlocomotion and deficits of prepulse inhibition. Following on, NRG1 retrodialysis (10 nM) reduced extracellular glutamate and glycine levels in the prefrontal cortex and hippocampus, and prevented PCP-induced increase in extracellular GABA levels in the hippocampus. CONCLUSION: With these results we provide the first compelling in vivo evidence for the involvement of NRG1 signaling in schizophrenia-relevant behavior and neurotransmission in the adult nervous system and highlight its treatment potential. Furthermore, the ability of NRG1 treatment to alter GABA, glutamate and glycine levels in the presence of PCP also suggests that NRG1 signaling has the potential to alter disrupted neurotransmission in patients with schizophrenia.
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    • "Animals displayed impaired theta burst-induced LTP compared to wild types, but deficits could be rescued by the application of recombinant NRG1. Remarkably, low to medium doses of recombinant doses of recombinant NRG1 led to an increase of LTP in mutant mice, while higher doses suppressed LTP (Bjarnadottir et al. 2007). These findings strongly support the idea that NRG1 influences synaptic plasticity in a dose-dependent way. "
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    ABSTRACT: Changes in fiber tract architecture have gained attention as a potentially important aspect of schizophrenia neuropathology. Although the exact pathogenesis of these abnormalities yet remains to be elucidated, a genetic component is highly likely. Neuregulin-1 (NRG1) is one of the best-validated schizophrenia susceptibility genes. We here report the impact of the Neuregulin-1 rs35753505 variant on white matter structure in healthy young individuals with no family history of psychosis. We compared fractional anisotropy in 54 subjects that were either homozygous for the risk C allele carriers (n = 31) for rs35753505 or homozygous for the T allele (n = 23) using diffusion tensor imaging with 3T. Tract-Based Spatial Statistics (TBSS), a method especially developed for diffusion data analysis, was used to improve white matter registration and to focus the statistical analysis to major fiber tracts. Statistical analysis showed that homozygous risk C allele carriers featured elevated fractional anisotropy (FA) in the right perihippocampal region and the white matter proximate to the left area 4p as well as the right hemisphere of the cerebellum. We found three clusters of reduced FA values in homozygous C allele carriers: in the left superior parietal region, the right prefrontal white matter and in the deep white matter of the left frontal lobe. Our results highlight the importance of Neuregulin-1 for structural connectivity of the right medial temporal lobe. This finding is in line with well known neuropathological findings in this region in patients with schizophrenia.
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    • "HPLC analysis conducted in TM-domain NRG1 mutants also demonstrated no changes in DA content or DA metabolite levels in the brain stem, PFC, hippocampus, and striatum (Desbonnet et al., 2012). However, the same mutant line did display hypophosphorylation of the NR2B subunit of the NMDA receptor (Bjarnadottir et al., 2007), as well as an increase in cortical 5-HT2A receptors and transporters (Dean et al., 2008). A recent study in NRG1 mutants employing receptor autoradiography found an increase in NMDA receptor levels in the cingulate, sensory, and motor cortices (Newell et al., 2013), with an age-dependent change in NMDA receptor expression in the accumbens and thalamus. "
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