Reciprocal signalling between NR2 subunits of the NMDA receptor and neuregulin1 and their role in schizophrenia

Abstract

. (2011) Reciprocal signalling between NR2 subunits of the NMDA receptor and neuregulin 1 and their role in schizophrenia, Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 35, no. 4, 1 June 2011 pp. 896-904. Reciprocal signalling between NR2 subunits of the NMDA receptor and neuregulin 1 and their role in schizophrenia AbstractSchizophrenia is a debilitating neurodevelopmental psychiatric disorder. Both the N-methyl-D-aspartate receptor (NMDAR) and neuregulin1 (NRG1) are key molecules involved in normal brain development that have been linked to schizophrenia pathology and aetiology. The NR2 proteins are critical structural and functional subunits of the NMDAR and are developmentally and spatially regulated. Altered NR2 gene and protein expression has been found in human post-mortem schizophrenia brain tissue together with changes in NRG1 and its receptor ErbB4. The NR2 subunits and ErbB4 share a common anchoring domain on the postsynaptic density and therefore a disruption to either of these molecules may influence the functioning of the other. It has been shown that NRG1 signalling can affect NMDAR levels and function, particularly phosphorylation of the NR2 subunits. However little is known about the possible effects of NMDAR dysfunction on NRG1 signalling, which is important with regards to schizophrenia aetiology as numerous risk factors for the disorder can alter NMDAR functioning during early brain development. This review focuses on the role of the NMDA receptor subunits and NRG1 signalling in schizophrenia and proposes a mechanism by which a disruption to the NMDAR, particularly via altering the balance of NR2 subunits during early development, could influence NRG1 signalling. Tables : 1 2 Abstract Schizophrenia is a debilitating neurodevelopmental psychiatric disorder. Both the Nmethyl-D-aspartate receptor (NMDAR) and neuregulin1 (NRG1) are key molecules involved in normal brain development that have been linked to schizophrenia pathology and aetiology. The NR2 proteins are critical structural and functional subunits of the NMDAR and are developmentally and spatially regulated. Altered NR2 gene and protein expression has been found in human post-mortem schizophrenia brain tissue together with changes in NRG1 and its receptor ErbB4. The NR2 subunits and ErbB4 share a common anchoring domain on the postsynaptic density and therefore a disruption to either of these molecules may influence the functioning of the other. It has been shown that NRG1 signalling can affect NMDAR levels and function, particularly phosphorylation of the NR2 subunits. However not much is known about the possible effects of NMDAR dysfunction on NRG1 signalling, which is important with regards to schizophrenia aetiology as numerous risk factors for the disorder can alter NMDAR functioning during early brain development. This review focuses on the role of the NMDA receptor subunits and NRG1 signalling in schizophrenia and proposes a mechanism by which a disruption to the NMDAR, particularly via the altering...

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

“…Similar to the DISC1 and neuregulin1 knockout mice, PSD95 homozygous KO's are not lethal, and the heterozygous animals share prepulse inhibition, hyperactivity, and enhanced LTP phenotypes (Desbonnet et al, 2009;Dyck et al, 2009;Kato et al, 2010;Le Greves et al, 2006;Yao et al, 2004). Interestingly, alterations in the localization and function of DISC1 and neuregulin1 are linked to abnormalities of the NMDA receptor signaling complex that includes PSD95 (Balu and Coyle, 2011;Geddes et al, 2011;Ma et al, 2013;Schmitt et al, 2011). The wellcharacterized effects of pharmacologic blockade of NMDA receptors, which yield a schizophreniform phenotype, support the hypothesis that disruption of synaptic plasticity, regardless of the mechanism, contributes to the signs and symptoms of schizophrenia.…”

“…Neuregulin1 modulates erbB signaling and neuregulin1 is believed to suppress NMDA receptor activation via this mechanism (Geddes et al, 2011;Golub et al, 2004;Hahn et al, 2006). In postmortem brain from subjects with schizophrenia, there was increased association between PSD95 and the tyrosine kinase erbB4, and an increase in neuregulin1-mediated suppression of NMDA receptor activity (Hahn et al, 2006).…”

mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia

“…Reduced NMDA-R expression in several brain regions, including the frontal cortex and hippocampus, has been found in individuals with schizophrenia (Errico et al, 2013;Geddes et al, 2014Geddes et al, , 2011Weickert et al, 2013). GABAA-R expression level differences vary between receptor subtypes and brain regions in individuals with schizophrenia (Benes et al, 1996a(Benes et al, , 1996bDuncan et al, 2010).…”

“…Substantial evidence from human and animal studies links an imbalance of excitatory glutamate and inhibitory gamma-aminobutyric acid (GABA) neurotransmission to the pathophysiology of schizophrenia (Javitt, 2010;Nakazawa et al, 2012). Recent studies report reduced expression of glutamatergic N-methyl-D-aspartate receptors (NMDA-R) and suggest an increase in glutamatergic state via activation of non-NMDA glutamate receptors in individuals with schizophrenia (Geddes et al, 2011;Hu et al, 2014;Moghaddam and Javitt, 2012;Nakazawa et al, 2012;Weickert et al, 2013). Furthermore, reduced expression levels of GABA synthesizing enzymes and transporters together with increased expression of GABAA receptors (GABAA-R) have been identified in several disease-relevant brain regions in individuals with schizophrenia (recently reviewed by Inan et al, 2013).…”

Differential effects of short- and long-term antipsychotic treatment on the expression of neuregulin-1 and ErbB4 receptors in the rat brain

“…NRG1-induced stimulation of the ErbB4 receptor activates several signalling pathways that are involved in multiple biological functions in neurodevelopment, including neuronal specification, neuronal migration, neuronal development, and plasticity of the adult brain (Geddes et al, 2011;Mei and Xiong, 2008;Rico and Marin, 2011). The NRG1 and ERBB4 genes were identified as major susceptibility genes for schizophrenia by many association studies in several ethnic groups (Liu et al, 2005;Nicodemus et al, 2010;Stefanis et al, 2013;Stefansson et al, 2002).…”