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Schizophrenia susceptibility pathway neuregulin 1–ErbB4 suppresses Src upregulation of NMDA receptors

Abstract

Hypofunction of the N-methyl D-aspartate subtype of glutamate receptor (NMDAR) is hypothesized to be a mechanism underlying cognitive dysfunction in individuals with schizophrenia. For the schizophrenia-linked genes NRG1 and ERBB4, NMDAR hypofunction is thus considered a key detrimental consequence of the excessive NRG1-ErbB4 signaling found in people with schizophrenia. However, we show here that neuregulin 1β–ErbB4 (NRG1β-ErbB4) signaling does not cause general hypofunction of NMDARs. Rather, we find that, in the hippocampus and prefrontal cortex, NRG1β-ErbB4 signaling suppresses the enhancement of synaptic NMDAR currents by the nonreceptor tyrosine kinase Src. NRG1β-ErbB4 signaling prevented induction of long-term potentiation at hippocampal Schaffer collateral–CA1 synapses and suppressed Src-dependent enhancement of NMDAR responses during theta-burst stimulation. Moreover, NRG1β-ErbB4 signaling prevented theta burst–induced phosphorylation of GluN2B by inhibiting Src kinase activity. We propose that NRG1-ErbB4 signaling participates in cognitive dysfunction in schizophrenia by aberrantly suppressing Src-mediated enhancement of synaptic NMDAR function.

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Figure 1: NRG1β-ErbB4 signaling prevents endogenous Src activation–induced potentiation of NMDAR-mediated synaptic responses in the hippocampal CA1.
Figure 2: NRG1β has no effect on basal NMDAR-mediated synaptic responses in hippocampal CA1 or in prefrontal cortex but prevents endogenous Src activation-induced potentiation of NMDAR EPSCs at prefrontal cortex synapses.
Figure 3: NRG1β prevents but does not reverse endogenous Src-induced synaptic potentiation.
Figure 4: NRG1β prevents but does not reverse TBS-induced LTP in CA1 hippocampus and has no effect in Src−/− mice.
Figure 5: NRG1β reduces depolarization of CA1 neurons during the period of TBS.
Figure 6: NRG1β does not alter Src association with the NMDAR but reduces Src tyrosine kinase activity and prevents TBS-induced GluN2B phosphorylation in hippocampal CA1.

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Acknowledgements

We thank J.F. MacDonald, P.A. Frankland, L.Y. Wang, M.F. Jackson and M.H. Pitcher for critical reading of the manuscript, and Genentech and L. Mei for providing NRG1β. Src knockout mice were obtained as a gift from B.F. Boyce, University of Rochester Medical Center. This study was supported by grants from the Canadian Institutes of Health Research (CIHR) to M.W.S. (MT-12682) and to E.K.L. (MOP-89825), and from the Deafness Research Foundation to K.T.Y. M.W.S. holds a Canada research chair (tier I) in neuroplasticity and pain, and is an International Research Scholar of the Howard Hughes Medical Institute. E.K.L. holds a Canada research chair (tier II) in developmental cortical physiology. G.M.P. was a CIHR postdoctoral fellow and was supported by a Merck Frosst Fellowship award. D.N. held a CIHR doctoral research award, L.V.K. was a CIHR MD-PhD student, and N.M.G. holds a CIHR Canada Graduate Scholarship doctoral award. We thank D. Wong, J. Hicks and S. Singhroy for technical support.

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G.M.P. designed the project, conducted the hippocampal experiments, analyzed the data and wrote the manuscript. L.V.K. and D.N. carried out and analyzed biochemical experiments. E.K.L. oversaw and analyzed the prefrontal cortex experiments. N.M.G. carried out and analyzed the prefrontal cortex experiments. K.T.Y. maintained, housed and provided ErbB4 knockout mice. All authors participated in revising the manuscript and agreed to the final version. M.W.S. conceived the study, analyzed data, supervised the overall project and wrote the manuscript.

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Correspondence to Michael W Salter.

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Pitcher, G., Kalia, L., Ng, D. et al. Schizophrenia susceptibility pathway neuregulin 1–ErbB4 suppresses Src upregulation of NMDA receptors. Nat Med 17, 470–478 (2011). https://doi.org/10.1038/nm.2315

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