A Model of Neuregulin Control of NMDA Receptors on Synaptic Spines

Abstract

Neuregulin (Nrg) through its receptor ErbB4 modulates the activity of the N-Methyl-D-Aspartate (NMDA) receptor (NMDAR) at synapses. As modification of this pathway has been implicated in schizophrenia, it is of great interest to define it in precise quantitative terms. Kinetic models of the epidermal growth factor (EGF)/ErbB receptor signalling pathway describing activation, desensitization, and tyrosine phosphorylation of EGFR/ErbB followed by binding and activation of Src family kinases that is subsequently followed by phosphorylation of target proteins are available. We have adapted these to give a kinetic description of NMDAR modulation by Nrg that recapitulates the observed kinetics of autophosphorylation of the ErbB dimer as well as the modulation of the NMDAR by Src kinase, according to whether the kinases are activated or deactivated. This quantitative description of the Nrg/NMDAR pathway provides a model for experimental elucidation of what goes awry in animal models of schizophrenia.

A blueprint for research on Shankopathies: A view from research on autism spectrum disorder

“…Heparan sulfate proteoglycan can binds to neuregulin, a ligand for the ErbB4 receptor tyrosine kinases at synapses (Jo et al, ). Both neuregulin and Erbb4 have been linked to schizophrenia (Stefansson et al, ; Hahn et al, ; Bennett et al, ). Since the proteins discussed above are all released with neural activity it will be important in the future to differentiate the effects of neurotransmitters from these co‐released proteins to help identify new and potentially therapeutic synaptogenic molecules.…”

Partial genetic deletion of neuregulin 1 and adolescent stress interact to alter NMDA receptor binding in the medial prefrontal cortex

“…Specifically, unlike WT mice whose dendritic morphology was unaffected by stress, repeated stress in Nrg1 HET mice reduced the length of dendrites and their complexity, and promoted an increase in dendritic spine density in pyramidal neurons of layers II/III of the anterior cingulate and PrL cortices of the medial prefrontal cortex. Given that Nrg1 and stress both influence NMDARs (Garcia et al, 2000 ; Bjarnadottir et al, 2007 ; Law et al, 2007 ; Li et al, 2007 ; Chong et al, 2008 ; Bennett, 2009 ; Cohen et al, 2010 ; Bennett et al, 2011 ; Buret and Van Den Buuse, 2014 ) and that NMDARs regulate the density of dendritic spines (Alvarez et al, 2007 ; Hayashi-Takagi et al, 2010 ) we hypothesized that Nrg1 and stress might interact to alter NMDAR binding specifically in the anterior cingulate and PrL cortices.…”

Schizophrenia: One Coat of Many Colors

“…Neuregulin (NRG) consists of a family of proteins that plays an essential role in several neurogenerative processes (Bennett, 2011; Ting et al, 2011; Bennett et al, 2012; Fleck et al, 2012). The NRG3 variant rs6584400 is associated with negative symptoms in schizophrenia (Meier et al, 2012).…”