Synaptic NR2A- but not NR2B-containing NMDA receptors increase with blockade of ionotropic glutamate receptors

Engelhardt, Jakob von; Doganci, Beril; Seeburg, Peter H.; Monyer, Hannah

doi:10.3389/neuro.02.019.2009

Cited by 23 publications

(16 citation statements)

References 66 publications

(95 reference statements)

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“…This is because NMDARs are regulated by receptor activity in a subtype‐specific manner. Compensatory upregulation of NR2A but not NR2B subunit‐containing receptors can change the NR2A/NR2B ratio as early as 4 hrs after MK‐801 application to generate a relative NR2B deficit . Acute application of selective NR2B antagonists also enhanced kainate‐induced GBO in vitro, similar to general antagonists of the NMDAR .…”

Section: Cellular Mechanisms Of Ketamine‐induced and Schizophrenia‐asmentioning

confidence: 91%

Impact of Ketamine on Neuronal Network Dynamics: Translational Modeling of Schizophrenia‐Relevant Deficits

et al. 2013

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Subanesthetic doses of the psychomimetic, ketamine, have been used for many years to elicit behavioral effects reminiscent of schizophrenia in both healthy humans and in animal models of the disease. More recently there has been a move towards the use of simple neurophysiological measures (event related potentials, brain oscillations) to assay the functional integrity of neuronal circuits in schizophrenia since these measures can be assessed in patients, healthy controls, intact animals, and even in brain slices. Furthermore, alterations of these measures are correlated with basic information processing deficits which are now considered central to the disease. Thus, here we review recent studies which determine the effect of ketamine on these measures and discuss to what extent they recapitulate findings in schizophrenic patients. In particular, we examine methodological differences between human and animal studies and compare in vivo and in vitro effects of ketamine. Ketamine acts on multiple cortical and subcortical sites, as well as on receptors other than the NMDA receptor. Acute ketamine models changes correlated with psychotic states (e.g. increased baseline gamma band oscillations) whereas chronic ketamine causes cortical circuit changes and neurophysiological deficits (e.g. impaired event- related gamma band oscillations) correlated with cognitive impairments in schizophrenia.

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Section: Cellular Mechanisms Of Ketamine‐induced and Schizophrenia‐asmentioning

confidence: 91%

Impact of Ketamine on Neuronal Network Dynamics: Translational Modeling of Schizophrenia‐Relevant Deficits

et al. 2013

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“…Following an 8 hour NMDAR blockade an increase in the insertion of new NR2A subunit containing NMDA receptors has also been found in hippocampal cell cultures, however no change in the NR2B subunit (von Engelhardt et al, 2009). Another study found that NR2A mRNA was significantly increased in the striatum, cortex and hippocampus 4 hours following MK-801 treatment to rats on PN7 .…”

Section: Nmda Receptor Subunits and Schizophreniamentioning

confidence: 99%

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

Geddes

Huang

Newell

2011

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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. (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...

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“…Generation of MolR:(palmitoylated)GFP:2a:Cre and MolR:(N-LS)mCherry was previously described (Lin et al, 2010). Retroviral constructs MolR:GFPGluN2A:2a:Cre and MolR:GFPGluN2B:2a:Cre were derived from previously published fusion proteins of NMDARs (von Engelhardt et al, 2009). Formation of functional channels by coexpression of GluN1 plasmids and MolR:GFPGluN2A:2a:Cre or MolR: GFPGluN2B:2a:Cre in HEK293 cells and recordings of NMDA-evoked currents (data not shown) confirmed that viral constructs delivered functional NMDAR subunits.…”

Section: Methodsmentioning

confidence: 99%

GluN2B-Containing NMDA Receptors Promote Wiring of Adult-Born Neurons into Olfactory Bulb Circuits

Kelsch

Eliava

et al. 2012

J. Neurosci.

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In the developing telencephalon, NMDA receptors (NMDARs) are composed of GluN1 and GluN2B subunits. These "young" NMDARs set a brake on synapse recruitment in neurons of the neonatal cortex. The functional role of GluN2B for synapse maturation of adult-born granule cells (GCs) in the olfactory bulb has not been established and may differ from that of differentiating neurons in immature brain circuits with sparse activity. We genetically targeted GCs by sparse retroviral delivery in mouse subventricular zone that allows functional analysis of single genetically modified cells in an otherwise intact environment. GluN2B-deficient GCs did not exhibit impairment with respect to the first developmental milestones such as synaptogenesis, dendrite formation, and maturation of inhibitory synaptic inputs. However, GluN2B deletion prevented maturation of glutamatergic synaptic input. This severe impairment in synaptic development was associated with a decreased response to novel odors and eventually led to the demise of adult-born GCs. The effect of GluN2B on GC survival is subunit specific, since it cannot be rescued by GluN2A, the subunit dominating mature NMDAR function. Our observations indicate that, GluN2B-containing NMDARs promote synapse activation in adult-born GCs that integrate in circuits with high and correlated synaptic activity. The function of GluN2B-containing NMDARs on synapse maturation can thus be bidirectional depending on the environment.

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Synaptic NR2A- but not NR2B-containing NMDA receptors increase with blockade of ionotropic glutamate receptors

Cited by 23 publications

References 66 publications

Impact of Ketamine on Neuronal Network Dynamics: Translational Modeling of Schizophrenia‐Relevant Deficits

Impact of Ketamine on Neuronal Network Dynamics: Translational Modeling of Schizophrenia‐Relevant Deficits

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

GluN2B-Containing NMDA Receptors Promote Wiring of Adult-Born Neurons into Olfactory Bulb Circuits

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