Neuregulin1 (NRG1) Signaling through Fyn Modulates NMDA Receptor Phosphorylation: Differential Synaptic Function in NRG1+/- Knock-Outs Compared with Wild-Type Mice

deCODE Genetics, 101 Reykjavik, Iceland.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 05/2007; 27(17):4519-29. DOI: 10.1523/JNEUROSCI.4314-06.2007
Source: PubMed


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.
    The International Journal of Neuropsychopharmacology 12/2014; DOI:10.1093/ijnp/pyu114 · 4.01 Impact Factor
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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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    ABSTRACT: Mutant mice play an increasingly important role in understanding disease processes at multiple levels. In particular, they illuminate the impact of risk genes for disease on such processes. This article reviews recent advances in the application of mutant mice to study the intricacies of dopaminergic (DAergic) function in relation to the putative pathophysiology of psychotic illness, particularly schizophrenia, and antipsychotic drug action. It considers models for understanding the role(s) of risk genes, with a particular focus on DTNBP1 and NRG1, their interactions with environmental factors, and with each other (epistasis). In overview, it considers new schemas for understanding psychotic illness that integrate DAergic pathophysiology with developmental, social, and cognitive processes, and how mutant mouse models can reflect and inform on such schemas.
    Progress in brain research 06/2014; 211:79-112. DOI:10.1016/B978-0-444-63425-2.00004-0 · 2.83 Impact Factor
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    • "Alterations in social and cognitive function have also been reported in these TMc-Nrg1+/− mutant mice, such as increased aggression, increased social recognition, decreased prepulse inhibition, and impaired contextual fear conditioning (Stefansson et al., 2002; O'Tuathaigh et al., 2007; Chesworth et al., 2012; Desbonnet et al., 2012). Furthermore, the involvement of Nrg1 in the modulation of cognitive functions has been further bolstered by in vitro electrophysiological studies in the hippocampus of EGF-like domain Nrg1+/− mice (Bjarnadottir et al., 2007). A recent study also indicated that ErbB4-null parvalbumin interneuron-restricted mutant mice and EGF-like domain Nrg1+/− mice exhibit increased hippocampal LTP (Shamir et al., 2012). "
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    ABSTRACT: Accumulating evidence suggests that neuregulin 1 (NRG1) might be involved in the neurodevelopment, neural plasticity, GABAergic neurotransmission, and pathogenesis of schizophrenia. NRG1 is abundantly expressed in the hippocampus, and emerging studies have begun to reveal the link between NRG1 signaling and cognitive deficits in schizophrenic patients. Because the transmembrane domain of NRG1 is vital for both forward and reverse signaling cascades, new Nrg1-deficient mice that carry a truncation of the transmembrane domain of the Nrg1 gene were characterized and used in this study to test a NRG1 loss-of-function hypothesis for schizophrenia. Both male and female Nrg1 heterozygous mutant mice and their wild-type littermates were used in a series of 4 experiments to characterize the impact of Nrg1 on behavioral phenotypes and to determine the importance of Nrg1 in the regulation of hippocampal neuromorphology and local GABAergic interneurons. First, a comprehensive battery of behavioral tasks indicated that male Nrg1-deficient mice exhibited significant impairments in cognitive functions. Second, pharmacological challenges were conducted and revealed that Nrg1 haploinsufficiency altered GABAergic activity in males. Third, although no genotype-specific neuromorphological alterations were found in the hippocampal CA1 pyramidal neurons, significant reductions in the hippocampal expressions of GAD67 and parvalbumin were revealed in the Nrg1-deficient males. Fourth, chronic treatment with valproate rescued the observed behavioral deficits and hippocampal GAD67 reduction in Nrg1-deficient males. Collectively, these results indicate the potential therapeutic effect of valproate and the importance of Nrg1 in the regulation of cognitive functions and hippocampal GABAergic interneurons, especially in males.
    Frontiers in Behavioral Neuroscience 04/2014; 8:126. DOI:10.3389/fnbeh.2014.00126 · 3.27 Impact Factor
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