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Pitcher GM, Kalia LV, Ng D, Goodfellow NM, Yee KT, Lambe EK, Salter MW. Schizophrenia susceptibility pathway neuregulin 1-ErbB4 suppresses Src upregulation of NMDA receptors. Nat Med . 2011 Apr ; 17(4):470-8. PubMed Abstract

Comments on Paper and Primary News
Comment by:  Amanda Jayne Law, SRF Advisor
Submitted 20 April 2011 Posted 20 April 2011

The study by Pitcher and colleagues incorporates a series of well-designed in-vitro experiments aimed at investigating the proposed link between NRG1-ErbB4 signaling, NMDAR activity, and synaptic function. Using wild-type and ErbB4 mutant mice (ErbB4-/-Her4heart), plus pharmacological inhibition of ErbB receptors, the study demonstrates that NRG1 signaling, via ErbB4, suppresses enhancement of NMDA receptors (NMDAR) via inhibition of the Src kinase, Src. Consistent with previous studies (see references 32-37 of Pitcher et al.), the authors demonstrate that NRG1 prevents induction of theta burst-induced LTP (tbLTP), and provide novel data to suggest that this requires Src. Mechanistically, the authors demonstrate that NRG1 is inhibitory to NMDAR EPSCs via blockade of Src. Activation of Src, via EPQ stimulation, results in increased NMDAR EPSC amplitudes; however, pretreatment of slices with soluble NRG1 prior to EPQ blocks the effects of EPQ on NMDAR EPSCs. Convincingly, the authors show that ErbB4 genetic deletion prevents the inhibitory effects of NRG1 on EPQ...  Read more

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Primary News: Neuregulin and ErbB4: Synaptic Jacks of All Trades

Comment by:  Michael CahillPeter Penzes
Submitted 29 April 2011 Posted 29 April 2011
  I recommend this paper

The recent study by Pitcher et al. provides a novel mechanism linking NRG1/ErbB4 activity to the suppression of NMDAR activity in a manner requiring Src kinase inhibition. The study uses biochemical manipulation of Src activation, as well as studies on cells lacking Src, to examine the role for Src kinase on the effects of NRG1 on NMDAR responses in pyramidal neurons. Overall, the study provides convincing evidence indicating that Src inhibition by NRG1 is an important contributor to the effects of NRG1 on NMDAR pyramidal neuronal hypofunction. The effect of NRG1 and ErbB4 on Src family kinase activation remains complex. Previous studies have found that NRG1 can activate Src, and that inhibition of Src family kinases can block some of the effects of NRG1 on cells, including cellular migration and proliferation (Eckert et al., 2009; Grossmann et al., 2009). Moreover, ErbB4 activity is able to activate fyn when overexpressed in heterologous cells, and NRG1 treatment activates fyn in...  Read more

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