Immunolocalization of NMDA receptor subunit NR3B in selected structures in the rat forebrain, cerebellum, and lumbar spinal cord

Wee, Karen Siaw-Ling; Zhang, Yibin; Khanna, Sanjay; Low, Chian-Ming

doi:10.1002/cne.21747

Cited by 67 publications

(59 citation statements)

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“…20 The anatomical distribution of the three known subunits of the NMDA receptor, NR1, NR2, and NR3, seems insufficiently specific to be closely correlated with distinct clinical symptoms. [21][22][23] In addition to paroxysmal movements, constant motor agitation was present in all individuals. R, right; L, left; P, partial; G, generalization; SE, status epilepticus; C, complex; TC, tonic-clonic.…”

Section: Discussionmentioning

confidence: 99%

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Severe childhood encephalopathy with dyskinesia and prolonged cognitive disturbances: evidence for anti‐N‐methyl‐d‐aspartate receptor encephalitis

Poloni

Korff

Ricotti

et al. 2010

Develop Med Child Neuro

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AIM We report four cases of acquired severe encephalopathy with massive hyperkinesia, marked neurological and cognitive regression, sleep disturbance, prolonged mutism, and a remarkably delayed recovery (time to full recovery between 5 and 18mo) with an overall good outcome, and its association with anti-N-methyl-D-aspartate (anti-NMDA) receptor antibodies.METHOD We reviewed the four cases retrospectively and we also reviewed the literature. RESULTS Anti-NMDA receptor antibodies (without ovarian teratoma detected so far) were found in the two children tested in this study. INTERPRETATIONThe clinical features are similar to those first reported in 1992 by Sebire et al., 1 and rarely recognized since. Sleep disturbance was not emphasized as part of the disorder, but appears to be an important feature, whereas coma is less certain and difficult to evaluate in this setting. The combination of symptoms, evolution (mainly seizures at onset), severity, paucity of abnormal laboratory findings, very slow recovery, and difficult management justify its recognition as a specific entity. The neuropathological substrate may be anatomically close to that involved in encephalitis lethargica, in which the same target functions (sleep and movement) are affected but in reverse, with hypersomnolence and bradykinesia. This syndrome closely resembles anti-NMDA receptor encephalitis, which has been reported in adults and is often paraneoplastic.In 1992, Sebire et al.1 reported a series of six children presenting with a novel combination of intense dyskinesia and severe regression with prolonged cognitive impairment but who made an unexpected excellent recovery.1 Since then, similar cases have been described. The disorder is sometimes called Sebire syndrome and is considered inflammatory or infectious in aetiology.2-5 Hartley et al., 6 in a paper entitled 'Immune-mediated chorea encephalopathy syndrome in childhood', specifically commented on the marked similarity between their cases and those of Sebire et al. Sleep disturbances (hypersomnolence) and dyskinesia (parkinsonism) are hallmarks of encephalitis lethargica, a condition increasingly recognized in children and presumed to be of autoimmune aetiology. In some cases, phases of insomnia and hyperkinesia, as in Sebire syndrome, may occur, suggesting that the localization of the acquired brain dysfunction may be in closely related areas and that common pathogenetic mechanisms are involved. This clinical picture is similar to the recently recognized entity, anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis, 7 which may be the underlying cause of the disorder reported by Sebire et al.We describe four new cases of Sebire syndrome, in which sleeplessness was a highly significant clinical feature 'masked' by severe dyskinesia and agitation, persisting long after dyskinesia had resolved. Anti-NMDA receptor antibodies were found in the two individuals who were tested. Their serum was analysed at the Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK (P...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Severe childhood encephalopathy with dyskinesia and prolonged cognitive disturbances: evidence for anti‐N‐methyl‐d‐aspartate receptor encephalitis

Poloni

Korff

Ricotti

et al. 2010

Develop Med Child Neuro

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“…However, recent investigations indicate a more widespread localization of NR3B, including its expression in cortex, cerebellum and hippocampus in the adult rat CNS [15,32]. In the human forebrain, NR3B mRNA is expressed in the CA1 to CA4 regions and dentate gyrus of the hippocampus [23].…”

Section: Expression Profile Of the Nr3 Subunitsmentioning

confidence: 98%

Shuffling the Deck Anew: How NR3 Tweaks NMDA Receptor Function

Cavara

Hollmann

2008

Mol Neurobiol

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The N-methyl-D -aspartate (NMDA) receptors are the most complex members in the family of ionotropic glutamate receptors. They are involved in long-term potentiation and underlie higher cognitive functions like memory formation and learning. On the other hand, overstimulation of NMDA receptors (NMDARs), leading to a massive influx of Ca(2+) ions into the cell, is linked to neurodegenerative disorders such as for example Huntington's disease and epilepsy. NMDARs are generally considered to be heteromeric tetramers and are conventionally thought to assemble from NR1 splice variants and NR2 subunits, which determine crucial channel properties. With the recent discovery of the functionally different NR3 subunits, many of the known features of NMDARs are being reassessed: The presence of NR3 in NMDARs decreases Mg(2+) sensitivity and Ca(2+) permeability and reduces agonist-induced current responses. Between altering those essential key characteristics of conventional NMDARs and forming a new class of excitatory glycine receptors when coassembling with NR1, the NR3 subunits give rise to a functionally entirely new array of "NMDA" receptors. Understanding the multifaceted influence of NR3 is imperative to further the understanding of the complex role of NMDARs in neurotransmission and higher brain functions.

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“…NR3B protein was found to be expressed in all of the substructures of the hippocampus (CA1, CA3, dentate gyrus); the various layers of the cerebral cortex, projection neurons, and interneurons of the striatum; different cell types of the cerebellum; and motor neurons of the spinal cord (Wee et al, 2008). In the cerebral cortex, NR3B immunoreactivity was detected in all of the layers.…”

Section: Nmda Receptor Nr3 Subunitsmentioning

confidence: 95%

“…On the other hand, NR3B expression was initially shown to be restricted to a few prominent regions such as the spinal cord, brain stem, cerebellum, and hippocampus (Nishi et al, 2001;Matsuda et al, 2002;Bendel et al, 2005). Recently, Wee et al (2008) reported a comprehensive study to systematically compare NR3B protein and NR1 localization across major brain regions. The study used immunolabeling with specific NR3B antibody on rat brain slices and revealed that there is a more widespread distribution of NR3B protein in the forebrain (hippocampus, cerebral cortex, caudoputamen, and nucleus accumbens), cerebellum, and lumbar sections of the spinal cord.…”

Section: Nmda Receptor Nr3 Subunitsmentioning

confidence: 99%

New Insights into the Not-So-New NR3 Subunits of N-Methyl-d-aspartate Receptor: Localization, Structure, and Function

Low¹,

Wee²

2010

Mol Pharmacol

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The NR3 subunits (NR3A and NR3B) are new players in a well established field of N-methyl-D-aspartate (NMDA) receptors, previously involving the NR1 and NR2 subunits. Their incorporation into conventional NMDA receptors forms glutamate-activated NR1/NR2/NR3 triheteromers, whereas the omission of the glutamate-binding NR2 subunits results in excitatory glycine-activated NR1/NR3 diheteromers. These NR3-containing NMDA receptors exhibit several differences in receptor properties compared with the conventional NR1/NR2 receptors. This review highlights the major landmarks that have been achieved in the past decade or so involving NR3 subunit research in four key areas: the spatiotemporal mapping of NR3 protein, the structural elucidation of NR3 domains, pharmacological characterization of NR3-containing receptors, and the successful generation of NR3 knockout/transgenic animals. It is expected that further characterization of their functional roles coupled with the identification of endogenous and exogenous ligands will eventually advance the understanding of the basic pharmacology and the complex role of NMDA receptors in higher brain functions and neurological disorders.The N-methyl-D-aspartate (NMDA) receptor is a subtype of the ionotropic glutamate (iGlu) receptors, a family of ligand-gated ion channels that mediates the majority of excitatory neurotransmission in the mammalian central nervous system. Named after the agonist originally used to differentiate this receptor from two other iGlu receptor members [␣-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) receptor and the 2-carboxy-3-carboxymethyl-4-isopropenylpyrrolidine (kainate) receptor], the NMDA receptor is unlike the other subtypes in three important ways. First, it requires both L-glutamate (agonist) and glycine (coagonist) for maximum activation (Johnson and Ascher, 1987;Kleckner and Dingledine, 1988;Dalkara et al., 1992). Second, the unique presence of an Mg 2ϩ channel blockade brings about a voltage-dependence property absent in other iGlu receptor members (Mayer et al., 1984;Nowak et al., 1984;Kupper et al., 1998). Third, the NMDA receptor exhibits relatively higher permeability to calcium ion (Ca 2ϩ ) than AMPA and kainate receptors, which links it to a variety of neurophysiological processes including neurodevelopment and cognition, and neuropathological conditions such as bipolar disorder, Parkinson's disease, and stroke (Dingledine et al

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Immunolocalization of NMDA receptor subunit NR3B in selected structures in the rat forebrain, cerebellum, and lumbar spinal cord

Cited by 67 publications

References 67 publications

Severe childhood encephalopathy with dyskinesia and prolonged cognitive disturbances: evidence for anti‐N‐methyl‐d‐aspartate receptor encephalitis

Severe childhood encephalopathy with dyskinesia and prolonged cognitive disturbances: evidence for anti‐N‐methyl‐d‐aspartate receptor encephalitis

Shuffling the Deck Anew: How NR3 Tweaks NMDA Receptor Function

New Insights into the Not-So-New NR3 Subunits of N-Methyl-d-aspartate Receptor: Localization, Structure, and Function

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