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The Journal of Neuroscience, April 25, 2007, 27(17):4519-4529; doi:10.1523/JNEUROSCI.4314-06.2007

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

Maria Bjarnadottir,^1 * Dinah L. Misner,^2 * Sascha Haverfield-Gross,¹ Silas Bruun,¹ Vignir G. Helgason,¹ Hreinn Stefansson,¹ Arnar Sigmundsson,¹ David R. Firth,¹ Berit Nielsen,¹ Ragnheidur Stefansdottir,¹ Thomas J. Novak,² Kari Stefansson,¹ Mark E. Gurney,¹ and Thorkell Andresson¹

¹deCODE Genetics, 101 Reykjavik, Iceland, and ²Roche Palo Alto, Palo Alto, California 94304

Correspondence should be addressed to Mark Gurney, deCODE Genetics, Sturlugata 8, 101 Reykjavik, Iceland. Email: mqurney{at}decode.com

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.

Key words: neuregulin; NMDAR; fyn; Src-family kinases; synaptic plasticity; schizophrenia

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Received Oct. 3, 2006; revised March 12, 2007; accepted March 13, 2007.

Correspondence should be addressed to Mark Gurney, deCODE Genetics, Sturlugata 8, 101 Reykjavik, Iceland. Email: mqurney{at}decode.com

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