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.Correspondence should be addressed to M.W.S. (mike.salter@utoronto.ca). 5 These authors contributed equally to this work.Note: Supplementary information is available on the Nature Medicine website. AUTHOR CONTRIBUTIONSG.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. COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests.Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/. Nat Med. Author manuscript; available in PMC 2012 January 23. CIHR Author Manuscript CIHR Author Manuscript CIHR Author ManuscriptThe NMDAR, a major excitatory ligand-gated ion channel in the central nervous system and a principal mediator of synaptic plasticity, is a multiprotein complex whose core is a heterotetramer comprising two obligate GluN1 subunits and two GluN2(A-D) subunits 1,2 . Proteins associated with the core NMDAR have key roles in trafficking, stability, subunit composition and function of NMDARs 3 . A key process regulating NMDAR activity is phosphorylation by NMDAR-associated kinases. Certain NMDAR-dependent functions, such as ventilation and locomotion, may be independent of NMDAR phosphorylation 4 , whereas phosphorylation-induced upregulation of NMDARs is critical for synaptic plasticity [5][6][7] .A prominent hypothesis for the pathophysiology of schizophrenia is that core symptoms such as...

Processing of Neuregulin-1 by Neuropsin Regulates GABAergic Neuron to Control Neural Plasticity of the Mouse Hippocampus

“…9A-C]. This observation is consistent with previous reports demonstrating a suppressive effect of mNRG-1 on LTP (Huang et al, 2000;Ma et al, 2003;Iyengar and Mott, 2008;Pitcher et al, 2008;Chen et al, 2010;Pitcher et al, 2011). By contrast, bath application of recombinant NRG-1 177-246 had no effect on basal synaptic strength in wild-type or neuropsin knock-out slices (see Fig.…”

“…LTP was induced by a single tetanic stimulation, which consisted of 100 stimuli delivered at 100 Hz at the test intensity. Recombinant human NRG-1 EGF-like domain [NRG-1 177-246 , a functional NRG-1 (Bjarnadottir et al, 2007;Chen et al, 2010;Pitcher et al, 2011); the EGF-like domain consists exactly of amino acid residues 177-246] (Peprotech) was applied to slices at 0.5 or 10 nM for 20 or 35 min after a stable baseline had been attained. ACSF was also supplemented as indicated with AG1478 (5 M; LC Laboratories) or bicuculline methiodide (Bicu) (10 M; Santa Cruz Biotechnology).…”

“…Recombinant NRG-1 has been reported to suppress protein synthesis-independent Schaffer-collateral LTP (E-LTP) in CA1 hippocampal synapses in the mouse brain (Huang et al, 2000;Ma et al, 2003;Kwon et al, 2005;Iyengar and Mott, 2008;Pitcher et al, 2008;Chen et al, 2010;Pitcher et al, 2011). Interestingly, previous studies have contradicted this suppressive effect and reported that NRG-1 potentiates tetanus-induced LTP in heterozygous mice deficient for the EGF domain of NRG-1, Nrg1(⌬EGF ) ϩ/Ϫ , although it had a similar suppressive effect on E-LTP in normal mouse hippocampal slices (Bjarnadottir et al, 2007;Role and Talmage, 2007).…”

Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia

“…A reduction in activity of the NRG1/ErbB3 signaling pathway also inhibits the Src kinase that is a regulator of the NMDAR. 19 Brain-derived neurotrophic factor (BDNF) and TrkB receptor dysfunction in schizophrenia. The expression of brainderived neurotrophic factor (BDNF) and its receptor TrkB are reduced in schizophrenia and this may have a major impact on the function of the inhibitory interneurons particularly during early development.…”

2640 – Exploring the pathogenetic association between schizophrenia and type 2 diabetes mellitus diseases based on pathway analysis

“…As a result, we found that 59 candidate genes have been connected to SCZ [34][35][36][37][38], 77 candidate genes have been linked to T2D [39][40][41][42][43], while 25 candidate genes [44][45][46][47][48][49] have been implicated to both SCZ and T2D with various studies (Additional file 5). Totally, 161 candidate genes (~45% of all candidate genes) have been related to either SCZ or T2D or both diseases with various experimental approaches, further proving the rationale of "function association" in the application of disease related gene inference.…”