title: 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.
authors: Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Graham M
authors: GM
authors: Pitcher
authors: Lorraine V
authors: LV
authors: Kalia
authors: David
authors: D
authors: Ng
authors: Nathalie M
authors: NM
authors: Goodfellow
authors: Kathleen T
authors: KT
authors: Yee
authors: Evelyn K
authors: EK
authors: Lambe
authors: Michael W
authors: MW
authors: Salter
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism; D004198:Disease Susceptibility; D004558:Electric Stimulation; D066246:ErbB Receptors / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008959:Models, Neurological; D020890:Neuregulin-1 / Q000378:metabolism* / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D066247:Receptor, ErbB-4; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012559:Schizophrenia / Q000209:etiology* / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D020890:Neuregulin-1; D016194:Receptors, N-Methyl-D-Aspartate; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; C587691:Erbb4 protein, rat; D066247:Receptor, ErbB-4; D019061:src-Family Kinases