Molecular determinants of NMDA receptor internalization

Roche, Katherine W.; Standley, Steve; McCallum, Jennifer; Ly, Calvin; Ehlers, Michael; Wenthold, Robert J.

doi:10.1038/90498

Cited by 472 publications

(488 citation statements)

References 48 publications

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“…Previous studies have shown that PSD-95 regulates NMDAR surface expression 30 and is involved in NMDAR-LTD A 16,17,39,40 .…”

Section: A Role For Psd-95 In Machr-ltd Nmentioning

confidence: 98%

“…Since hippocalcin interacts with the clathrin adaptor protein AP2 15 and since AP2 is involved in the internalisation of NMDARs, where it might compete with PSD-95 30 , we investigated the interactions of these three molecules with NMDAR subunits, using co-immunoprecipitation (co-IP) assays (Fig. 6a).…”

Section: Psd-95mentioning

confidence: 99%

“…It was already known that NMDARs can undergo clathrin-mediated endocytosis but the trigger for, and functional significance of, this process was unknown. Previous work has shown that PSD-95 and -adaptin can bind to a similar region of the intracellular tail of GluN2B subunits and it was therefore suggested that the function of PSD-95 might be to inhibit clathrin-mediated endocytosis 30 . Here we provided further experimental support for this hypothesis and have identified a potential molecular mechanism.…”

Section: A Role For Hippocalcin In Machr-ltd Nmentioning

confidence: 99%

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Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95

et al. 2010

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“…Previous studies have shown that PSD-95 regulates NMDAR surface expression 30 and is involved in NMDAR-LTD A 16,17,39,40 .…”

Section: A Role For Psd-95 In Machr-ltd Nmentioning

confidence: 98%

Section: Psd-95mentioning

confidence: 99%

Section: A Role For Hippocalcin In Machr-ltd Nmentioning

confidence: 99%

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Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95

et al. 2010

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“…Our interpretation of the reduced synaptic immunoreactivity is that the NMDA receptor blockade causes net trafficking of NR2B subunits away from the active zone of synapses and also out of spines and terminals. NR2B subunits are known to be rapidly internalized in immature neurons (Roche et al, 2001). Activity-dependent trafficking of synaptic NR2B-containing receptors has been shown anatomically using in vitro fluorescent preparations (Rao and Craig, 1997), electrophysiologically (Tovar and Westbrook, 2002), and biochemically (Grosshans et al, 2002).…”

Section: D-apv Causes Trafficking Of Nr2b Subunits Away From Synapsesmentioning

confidence: 99%

“…Among the NR2 subunits, the NR2A and NR2B subtypes are the most prevalent in the cerebral cortex (Watanabe et al, 1992), and of the two, the NR2B subunits are shown to be particularly influential in learning and memory (Tang et al, 1999;Tang and Schuman, 2002) as they prolong NMDA receptor currents, thus allowing greater Ca influx (Mori and Mishina, 1995;Dingledine et al, 1999). Further, Roche et al (2001) have shown that the C-terminus of NR2B subunit is sufficient for rapid internalization of the NMDA receptor.The present study focused on activity-dependent trafficking of endogenous NR2B subunits in adult rat cortex. We applied a competitive NMDA receptor antagonist, D-2-amino-5-phosphonovalerate (D-APV), onto one hemisphere of intact anesthetized, adult rat cortices.…”

mentioning

confidence: 99%

In vivo blockade of N-methyl-d-aspartate receptors induces rapid trafficking of NR2B subunits away from synapses and out of spines and terminals in adult cortex

Fujisawa

Aoki

2003

Neuroscience

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We investigated the role of in vivo synaptic activity upon trafficking of the N-methyl-D-aspartate (NMDA) receptor subunit, NR2B, at mature synapses by electron microscopic immunocytochemistry. In vivo blockade of NMDA receptors was achieved by applying the NMDA receptor antagonist, D-2-amino-5-phosphonovalerate (D-APV), onto the cortical surface of one hemisphere of anesthetized adult rats. Inactive L-2-amino-5-phosphonovalerate (L-APV) was applied to the contralateral hemisphere for within-animal control and to assess basal level of NR2B subunits at synapses. Within 30 min of D-APV treatment, we observed a decrease in the number of layer I axospinous asymmetric synapses that are positively immuno-labeled for the NR2B subunits. This decrease was paralleled by reductions in the absolute number of immuno-gold particles found at these synapses. The decrease of NR2B labeling was detectable in all five animals examined. Significant reductions were seen not only at post-synaptic densities, but also within the cytoplasm of spines and axon terminals. The data demonstrate that blockade of NMDA receptors induces trafficking of NR2B subunits out of synaptic membranes, spines, and terminals. This is in sharp contrast to a previous observation that NR2A subunits move into spines and axon terminals following in vivo blockade with D-APV. These findings point to yet unknown, NMDA receptor activitydependent mechanisms that separately regulate the localization of NR2A and NR2B subunits at synapses. Keywordsactivity-dependent; D-APV; electron microscopy; immunocytochemistry; ultrastructure; postembedding colloidal gold labelingThe N-methyl-D-aspartate (NMDA) subtype of glutamate receptor plays an important role in experience-dependent plasticity. Calcium influx through this receptor can trigger a variety of downstream biochemical reactions, contributing to plasticity (Mori and Mishina, 1995;Kind and Neumann, 2001) and excitotoxicity (Lynch and Guttmann, 2002). One of many consequences of NMDA receptor activation is altered trafficking of proteins to and from the activated synapses. For example, long-term potentiation, in which the electrophysiological response to an input is augmented, is in part produced by NMDA receptor-dependent upregulation of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (see NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2010 May 24. Malenka and Nicoll, 1999). In vitro and fewer in vivo preparations have been used to demonstrate that NMDA receptors, too, are removed from or inserted into synaptic membrane (Rao and Craig, 1997;Liao et al., 1999;Quinlan et al., 1999;Heynen et al., 2000;Barria and Malinow, 2002;Grosshans et al., 2002;Tovar and Westbrook, 2002). However, since nearly all of these studies have used neonatal tissues, whether or not such dynamic properties of NMDA receptor subunits persist at mature synapses, in vivo, is a topic that remains relatively unexplored.Among the NMDA receptor subunits, the NR1 is necessary for NMD...

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Acute mechanisms underlying antibody effects in anti–N‐methyl‐D‐aspartate receptor encephalitis

Moscato

Peng

Jain

et al. 2014

Annals of Neurology

296

290

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ObjectiveA severe but treatable form of immune-mediated encephalitis is associated with antibodies in serum and cerebrospinal fluid (CSF) against the GluN1 subunit of the N-methyl-D-aspartate receptor (NMDAR). Prolonged exposure of hippocampal neurons to antibodies from patients with anti-NMDAR encephalitis caused a reversible decrease in the synaptic localization and function of NMDARs. However, acute effects of the antibodies, fate of the internalized receptors, type of neurons affected, and whether neurons develop compensatory homeostatic mechanisms were unknown and are the focus of this study.MethodsDissociated hippocampal neuron cultures and rodent brain sections were used for immunocytochemical, physiological, and molecular studies.ResultsPatient antibodies bind to NMDARs throughout the rodent brain, and decrease NMDAR cluster density in both excitatory and inhibitory hippocampal neurons. They rapidly increase the internalization rate of surface NMDAR clusters, independent of receptor activity. This internalization likely accounts for the observed decrease in NMDAR-mediated currents, as no evidence of direct blockade was detected. Once internalized, antibody-bound NMDARs traffic through both recycling endosomes and lysosomes, similar to pharmacologically induced NMDAR endocytosis. The antibodies are responsible for receptor internalization, as their depletion from CSF abrogates these effects in hippocampal neurons. We find that although anti-NMDAR antibodies do not induce compensatory changes in glutamate receptor gene expression, they cause a decrease in inhibitory synapse density onto excitatory hippocampal neurons.InterpretationOur data support an antibody-mediated mechanism of disease pathogenesis driven by immunoglobulin-induced receptor internalization. Antibody-mediated downregulation of surface NMDARs engages homeostatic synaptic plasticity mechanisms, which may inadvertently contribute to disease progression. Ann Neurol 2014;76:108–119

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Molecular determinants of NMDA receptor internalization

Cited by 472 publications

References 48 publications

Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95

Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95

In vivo blockade of N-methyl-d-aspartate receptors induces rapid trafficking of NR2B subunits away from synapses and out of spines and terminals in adult cortex

Acute mechanisms underlying antibody effects in anti–N‐methyl‐D‐aspartate receptor encephalitis

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