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: 6.75). 05/2007; 27(17):4519-29. DOI: 10.1523/JNEUROSCI.4314-06.2007
Source: PubMed

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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    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 · 5.26 Impact Factor
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    ABSTRACT: Neuregulin-1 (NRG1) and ErbB4 genes have been identified as candidate genes for schizophrenia. Post-mortem studies indicated that NRG1-ErbB4 signalling is impaired in schizophrenia subjects. This study investigated whether short- or long-term antipsychotic treatment has different effects on the expression of NRG1 and ErbB4 receptors. Female Sprague-Dawley rats were treated orally with either aripiprazole (0.75mg/kg), haloperidol (0.1mg/kg), olanzapine (0.5mg/kg), or vehicle, 3 times/day for 1 or 12 weeks. Western blotting was performed to examine the expression of NRG1 isoforms (135kDa, 70kDa and 40kDa) and ErbB4 receptors. Both 1-week haloperidol and olanzapine treatment increased NRG1-70kDa expression in the hippocampus; haloperidol also up-regulated ErbB4 levels in the prefrontal cortex (PFC). In the 12-week group, aripiprazole decreased the expression of all three NRG1 isoforms and ErbB4 receptors in the PFC, NRG1-70kDa and -40kDa in the cingulate cortex (Cg), and NRG1-135kDa, -70kDa and ErbB4 receptors in the hippocampus; haloperidol reduced NRG1-135kDa in the PFC, NRG1-40kDa in all three brain regions, and ErbB4 receptor levels in the PFC and hippocampus; NRG1-40kDa in the PFC and Cg was also down-regulated by olanzapine. These results suggest that the time-dependent and region-specific effects of antipsychotics on NRG1-ErbB4 signalling may contribute to the efficacy of antipsychotics to treat schizophrenia. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Psychiatry Research 12/2014; 225(3). DOI:10.1016/j.psychres.2014.12.014 · 2.68 Impact Factor
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    ABSTRACT: Synaptic plasticity alters the strength of information flow between presynaptic and postsynaptic neurons and thus modifies the likelihood that action potentials in a presynaptic neuron will lead to an action potential in a postsynaptic neuron. As such, synaptic plasticity and pathological changes in synaptic plasticity impact the synaptic computation which controls the information flow through the neural microcircuits responsible for the complex information processing necessary to drive adaptive behaviors. As current theories of neuropsychiatric disease suggest that distinct dysfunctions in neural circuit performance may critically underlie the unique symptoms of these diseases, pathological alterations in synaptic plasticity mechanisms may be fundamental to the disease process. Here we consider mechanisms of both short-term and long-term plasticity of synaptic transmission and their possible roles in information processing by neural microcircuits in both health and disease. As paradigms of neuropsychiatric diseases with strongly implicated risk genes, we discuss the findings in schizophrenia and autism and consider the alterations in synaptic plasticity and network function observed in both human studies and genetic mouse models of these diseases. Together these studies have begun to point toward a likely dominant role of short-term synaptic plasticity alterations in schizophrenia while dysfunction in autism spectrum disorders (ASDs) may be due to a combination of both short-term and long-term synaptic plasticity alterations.
    Frontiers in Synaptic Neuroscience 11/2014; 6:28. DOI:10.3389/fnsyn.2014.00028


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Sep 19, 2014