NMDA Receptor Subunits Have Differential Roles in Mediating Excitotoxic Neuronal Death Both<i>In Vitro</i>and<i>In Vivo</i>

Liu, Yitao; Wong, Tak Pan; Aarts, Michelle; Rooyakkers, Amanda; Liu, Lidong; Lai, Ted Weita; Wu, Dong; Lu, Jie; Tymianski, Michael; Craig, Ann Marie; Wang, Yu Tian

doi:10.1523/jneurosci.0116-07.2007

Cited by 699 publications

(673 citation statements)

References 74 publications

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“…NR2B is expressed during processes involving oligodendrocytes, and NMDA receptors are extremely sensitive to ischemia (25). Also, activation of NR2B-containing NMDA receptors results in excitotoxicity, whereas activation of NR2A-containing NMDA receptors promotes neuronal survival (15). In accordance with these findings, NR2B was the only NMDA subunit that showed early significant down-regulation in mouse pups subjected to gestational hypoxia.…”

Section: Discussionsupporting

confidence: 56%

“…The occurrence of CP may depend, at least in part, on polymorphisms in genes for TNF-␣ and mannose-binding lectin (11-13). The genetic regulation of glutamate-receptor expression also has a major role throughout development and responds to changes in the cerebral environment (14,15).We recently showed that protracted prenatal hypoxia in rats caused dramatic WMD in the pups, with microgial activation and oligodendrocyte death leading to deficient myelination (16). To investigate a potential role for genetic factors, we compared brain damage in mouse and rat pups subjected to similar levels of antenatal hypoxia.…”

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confidence: 99%

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confidence: 99%

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Vulnerability of white matter towards antenatal hypoxia is linked to a species-dependent regulation of glutamate receptor subunits

Fontaine

Olivier

Massonneau

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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White-matter damage is a leading cause of neurological handicap. Although hypoxia-ischemia and excitotoxicity are major pathogenic factors, a role for genetic influences was suggested recently. Thus, protracted gestational hypoxia was associated with whitematter damage (WMD) in rat pups but not in mouse pups. Indeed, microglial activation and vessel-wall density on postnatal days (P)1 and P10 were found increased in both mouse and rat pups, but cell death, astrogliosis, and myelination were only significantly altered in hypoxic rat pups. We investigated whether this species-related difference was ascribable to effects of antenatal hypoxia on the expression of glutamate receptor subunits by using immunocytochemistry, PCR, and excitotoxic double hit insult. Quantitative PCR in hypoxic mouse pups on P1 showed 2-to 4-fold down-regulation of the AMPA-receptor subunits -1, 2, and -4; of the kainate-receptor subunit GluR7; and of the metabotropic receptor subunits mGluR1, -2, -3, -5, and -7. None of the glutamate-receptor subunits was down-regulated in the hypoxic rat pups. NR2B was the only NMDA-receptor subunit that was down-regulated in hypoxic mice but not in hypoxic rat on P1. Ifenprodil administration to induce functional inhibition of NMDA containing NR2B-subunit receptors prevented hypoxia-induced myelination delay in rat pups. Intracerebral injection of a glutamate agonist produced a larger decrease in ibotenate-induced excitotoxic lesions in hypoxic mouse pups than in normoxic mouse pups. Gestational hypoxia may regulate the expression of specific glutamate-receptor subunits in fetal mice but not in fetal rats. Therefore, genetic factors may influence the susceptibility of rodents to WMD. brain damage ͉ NMDA receptors ͉ genetic factors ͉ development ͉ prematurity P eriventricular (P) WMD and subsequent cortical damage are the leading causes of cerebral palsy (CP) limited to preterm birth (1, 2). Animal models have been developed to unravel the mechanisms underlying these brain lesions. Factors that seem involved in the pathophysiology of CP in these models include hypoxia and ischemia, infection and inflammation, excitotoxicity, accumulation of reactive oxygen species, and deficiencies in growth factors (3, 4). These factors seem to act in combination to cause damage to the developing white matter.Glutamate accumulation may be a mechanism common to many risk factors for CP. Glutamate, the major excitatory neurotransmitter, acts by means of several groups of receptors, namely, NMDA, AMPA, kainate, and metabotropic receptors (mGluRs). Excessive activation of glutamate receptors may cause cell vulnerability, in part as a result of intracellular calcium influx (5, 6). Intracerebral injection of glutamate agonists into the neocortex and white matter of newborn rodents produces histological lesions that mimic the brain damage observed in preterm neonates (7-10).Several studies suggest that genetic factors may influence the susceptibility of very preterm infants to PWMD. The occurrence of CP may depend, at least in ...

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Section: Discussionsupporting

confidence: 56%

mentioning

confidence: 99%

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Vulnerability of white matter towards antenatal hypoxia is linked to a species-dependent regulation of glutamate receptor subunits

Fontaine

Olivier

Massonneau

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…It is now well admitted that NMDAR differentially control neuronal outcome depending on either their cellular localization 26 and/or their composition in subunit 27 and/or their anchorage with cytoplasmic or membrane-associated proteins. 22 In this study, we first show that NMDAR-dependent Erk( 1 2 ) activation is potentiated by both exogenous and endogenous tPA and that its catalytic activity of tPA is a necessary event.…”

Section: Discussionmentioning

confidence: 99%

NR2D-containing NMDA receptors mediate tissue plasminogen activator-promoted neuronal excitotoxicity

et al. 2009

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Although the molecular bases of its actions remain debated, tissue-type plasminogen activator (tPA) is a paradoxical brain protease, as it favours some learning/memory processes, but increases excitotoxic neuronal death. Here, we show that, in cultured cortical neurons, tPA selectively promotes NR2D-containing N-methyl-D-aspartate receptor (NMDAR)-dependent activation. We show that tPA-mediated signalling and neurotoxicity through the NMDAR are blocked by co-application of an NR2D antagonist (phenanthrene derivative (2S*, 3R*)-1-(phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid, PPDA) or knockdown of neuronal NR2D expression. In sharp contrast with cortical neurons, hippocampal neurons do not exhibit NR2D both in vitro and in vivo and are consequently resistant to tPA-promoted NMDAR-mediated neurotoxicity. Moreover, we have shown that activation of synaptic NMDAR prevents further tPA-dependent NMDAR-mediated neurotoxicity and sensitivity to PPDA. This study shows that the earlier described pro-neurotoxic effect of tPA is mediated by NR2D-containing NMDARdependent extracellular signal-regulated kinase activation, a deleterious effect prevented by synaptic pre-activation.

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“…For example, Hardingham and colleagues reported that NR2B receptors in extrasynaptic locations mediate cell death via abrogated CREB signaling . In addition, Liu et al (2007) reported that NR2B subunit-containing NMDA receptors, whether synaptic or extrasynaptic, mediate harmful cell signaling, whereas NR2A subunit-containing NMDA receptors appear protective. Our data and that of Sattler et al (2000) suggest that toxic ischemia-induced NMDA signaling is inhibited after loss of dendritic spines; however, the effect of dendritic spine collapse on NMDA receptor function is not yet fully clear and requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin–Proteasome-Mediated Synaptic Reorganization: A Novel Mechanism Underlying Rapid Ischemic Tolerance

Meller¹,

Thompson²,

Lusardi³

et al. 2008

J. Neurosci.

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Ischemic tolerance is an endogenous neuroprotective mechanism in brain and other organs, whereby prior exposure to brief ischemia produces resilience to subsequent normally injurious ischemia. Although many molecular mechanisms mediate delayed (genemediated) ischemic tolerance, the mechanisms underlying rapid (protein synthesis-independent) ischemic tolerance are relatively unknown. Here we describe a novel mechanism for the induction of rapid ischemic tolerance mediated by the ubiquitin-proteasome system. Rapid ischemic tolerance is blocked by multiple proteasome inhibitors [carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG132), MG115 (carbobenzoxy-L-leucyl-L-leucyl-L-norvalinal), and clasto-lactacystin-␤-lactone].A proteomics strategy was used to identify ubiquitinated proteins after preconditioning ischemia. We focused our studies on two actin-binding proteins of the postsynaptic density that were ubiquitinated after rapid preconditioning: myristoylated, alanine-rich C-kinase substrate (MARCKS) and fascin. Immunoblots confirm the degradation of MARCKS and fascin after preconditioning ischemia. The loss of actin-binding proteins promoted actin reorganization in the postsynaptic density and transient retraction of dendritic spines. This rapid and reversible synaptic remodeling reduced NMDA-mediated electrophysiological responses and renders the cells refractory to NMDA receptor-mediated toxicity. The dendritic spine retraction and NMDA neuroprotection after preconditioning ischemia are blocked by actin stabilization with jasplakinolide, as well as proteasome inhibition with MG132. Together these data suggest that rapid tolerance results from changes to the postsynaptic density mediated by the ubiquitin-proteasome system, rendering neurons resistant to excitotoxicity.

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NMDA Receptor Subunits Have Differential Roles in Mediating Excitotoxic Neuronal Death BothIn VitroandIn Vivo

Cited by 699 publications

References 74 publications

Vulnerability of white matter towards antenatal hypoxia is linked to a species-dependent regulation of glutamate receptor subunits

Vulnerability of white matter towards antenatal hypoxia is linked to a species-dependent regulation of glutamate receptor subunits

NR2D-containing NMDA receptors mediate tissue plasminogen activator-promoted neuronal excitotoxicity

Ubiquitin–Proteasome-Mediated Synaptic Reorganization: A Novel Mechanism Underlying Rapid Ischemic Tolerance

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