Receptor TraffickingReviewSurface trafficking of N-methyl-d-aspartate receptors: Physiological and pathological perspectives
Section snippets
NMDAR structure and intracellular trafficking: Overview
Over the last decades, the NMDAR has emerged as one key regulator of the glutamatergic synaptic transmission. The glutamatergic synapses undergo various forms of NMDAR-dependent long-lasting changes in strength, a process thought to underlie some forms of learning and memory (Malenka and Nicoll, 1999). NMDARs are heteromeric molecules formed of NR1, NR2, and NR3 subunits, which themselves contain several variants: a single NR1 subunit with eight splice variants, four NR2 subunits (NR2AāD), and
Surface distribution of NMDARS: Heterogeneous within and between neuronal types
As mentioned above, little is known about the surface distribution of NMDARs. An overview of surface NMDARs in different neuronal cell types and synaptic populations reveals clear heterogeneous distributions, with clustered and non-clustered receptors, and a segregation of distinct NMDAR subtypes (e.g. different subunit composition) in certain membrane compartments. First, surface NMDARs can be classified depending on their spatial localization and functional specificities. Schematically, three
NMDAR surface trafficking: Evidences and subunit dependence
The interest for the surface trafficking of neurotransmitter receptors is quite recent and our current understanding is consequently limited. Still, receptor surface diffusion has emerged as a key pathway for receptor trafficking to and from synapses. The presence of a specialization zone dedicated to endocytosis has been described either laterally to the PSD of glutamatergic synapse or extrasynaptically (Blanpied et al., 2002) and exocytosis of AMPAR has been shown to take place mostly outside
Can the surface trafficking of NMDAR be regulated?
Before examining the few evidences that demonstrate a regulation of NMDAR surface diffusion, it is interesting to note that different neurotransmitter receptor types exhibit different surface diffusions. For instance, AMPAR surface diffusion is higher than that of NMDARs (Groc et al., 2004). This difference was striking in the extrasynaptic membrane where GluR2-AMPARs display higher diffusion coefficients and a higher proportion of mobile receptors than that of NR1-NMDARs. This suggests that at
Synaptic retention of NMDARS: Multiple interactions?
Clearly, less is known about the molecular mechanisms involved in the synaptic retention of NMDARs when compared with AMPARs. Still changes in NMDAR subtypes and/or number occur at the synapse during synaptic maturation, plasticity, or homeostatic regulation. Interestingly, although more functional NMDARs are produced and inserted in the plasma membrane by overexpression of either NR2A or NR2B subunit, no change in the number of synaptic functional NMDARs is observed (Prybylowski et al., 2002).
Synaptic maturation and NMDAR surface trafficking: A close interplay?
The contribution of NMDARs to the maturation and refinement of neuronal connections is essential, through both ionotropic and structural signaling (Colonnese and Constantine-Paton 2006, Colonnese et al 2003, Alvarez et al 2007). During development, the subunit composition of synaptic NMDARs changes from heterodimers containing predominantly NR2B subunits at early stages to heterodimers containing NR1-2B-NMDARs, NR1-2A-NMDARs, and NR1-2A-2B-NMDARs at a mature stage (Tovar and Westbrook 1999,
Extrasynaptic NMDARS: Emerging functions
What is the function of extrasynaptic NMDARs? Although this question is far from answered, we earlier hypothesized that these NMDARs serve as reserve pool that is mobilized on demand for lateral exchange of synaptic NMDARs. The implicit meaning of such a hypothesis is that extrasynaptic NMDARs do not have a function per se except to sustain synaptic NMDAR signaling. This view is likely wrong and the diversity of extrasynaptic NMDAR functions is only rising (Fig. 4). It is for instance puzzling
Activation of NMDARS: Physiological versus pathological signaling
Altered NMDAR signaling is a hallmark of several psychiatric and neurological disorders. Consistently, attempts have been made to use NMDAR antagonists to reduce or prevent some symptoms in these diseases but results are still unsatisfactory and efforts are necessary to develop new targets and drugs (Chen and Lipton, 2006). Among the psychiatric disorders, NMDAR hypofunction has been implicated since several decades in the behavioral manifestations (e.g. motor stereotypy and social withdrawal)
Conclusion
The understanding of NMDAR cellular trafficking has captured a lot of attention over the last decades. Recent evidences have demonstrated that, in addition to cycling between intracellular and membrane compartments, NMDARs diffuse at the surface of neurons which adds another level of complexity. For instance, the number and subtypes of synaptic NMDARs are most likely controlled by both surface trafficking and cycling processes. As for other glutamatergic receptors, it emerges that receptor
Acknowledgments
Work supported by grants from the Centre National de la Recherche Scientifique, Conseil RĆ©gional d'Aquitaine, MinistĆØre de la Recherche, Fondation pour la recherche mĆ©dicale and European Community grant (GRIPANT, CT-2005-005320). Due to space limitations all references related to the NMDA receptor trafficking field were not included in this review and we thus apologize to colleagues from which work was not cited.
References (148)
- et al.
Photoinactivation of native AMPA receptors reveals their real-time trafficking
Neuron
(2005) - et al.
Subunit-specific NMDA receptor trafficking to synapses
Neuron
(2002) - et al.
NMDA receptor subunit composition controls synaptic plasticity by regulating binding to CaMKII
Neuron
(2005) - et al.
The interaction between stargazin and PSD-95 regulates AMPA receptor surface trafficking
Neuron
(2007) - et al.
Rapid bidirectional switching of synaptic NMDA receptors
Neuron
(2007) Developing networks play a similar melody
Trends Neurosci
(2001)- et al.
Tonic facilitation of glutamate release by presynaptic N-methyl-D-aspartate autoreceptors in the entorhinal cortex
Neuroscience
(1996) - et al.
Dynamics and regulation of clathrin coats at specialized endocytic zones of dendrites and spines
Neuron
(2002) - et al.
Regulation of NMDA receptors by phosphorylation
Neuropharmacology
(2007) - et al.
EphB receptors interact with NMDA receptors and regulate excitatory synapse formation
Cell
(2000)
Matrix metalloproteinases and their endogenous inhibitors in neuronal physiology of the adult brain
FEBS Lett
A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain
Neuron
Input-specific targeting of NMDA receptor subtypes at mouse hippocampal CA3 pyramidal neuron synapses
Neuropharmacology
Kinetics and Mg2+ block of N-methyl-D-aspartate receptor channels during postnatal development of hippocampal CA3 pyramidal neurons
Neuroscience
Disruption of the NMDA receptor-PSD-95 interaction in hippocampal neurons with no obvious physiological short-term effect
Neuropharmacology
To model a psychiatric disorder in animals: schizophrenia as a reality test
Neuropsychopharmacology
Paradox of Ca2+ signaling, cell death and stroke
Trends Neurosci
Developmental and regional expression in the rat brain and functional properties of four NMDA receptors
Neuron
Role of the carboxy-terminal region of the GluR epsilon2 subunit in synaptic localization of the NMDA receptor channel
Neuron
Increased ethanol resistance and consumption in Eps8 knockout mice correlates with altered actin dynamics
Cell
Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions
Science
NMDA di-heteromeric receptor populations and associated proteins in rat hippocampus
J Neurosci
Distinct structural and ionotropic roles of NMDA receptors in controlling spine and synapse stability
J Neurosci
Schaffer collateral and perforant path inputs activate different subtypes of NMDA receptors on the same CA1 pyramidal cell
Br J Pharmacol
Arg-Gly-Asp-Ser-selective adhesion and the stabilization of long-term potentiation: pharmacological studies and the characterization of a candidate matrix receptor
J Neurosci
Transition from reversible to persistent binding of CaMKII to postsynaptic sites and NR2B
J Neurosci
N-methyl-D-aspartate receptors are clustered and immobilized on dendrites of living cortical neurons
Proc Natl Acad Sci U S A
NR2B and NR2D subunits coassemble in cerebellar Golgi cells to form a distinct NMDA receptor subtype restricted to extrasynaptic sites
J Neurosci
NR2B- and NR2D-containing synaptic NMDA receptors in developing rat substantia nigra pars compacta dopaminergic neurones
J Physiol
Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence
Annu Rev Pharmacol Toxicol
Activity-dependent decrease in NMDA receptor responses during development of the visual cortex
Science
Chronic ethanol induces synaptic but not extrasynaptic targeting of NMDA receptors
J Neurosci
Prolonged synaptic currents and glutamate spillover at the parallel fiber to stellate cell synapse
J Neurosci
Generation of slow network oscillations in the developing rat hippocampus after blockade of glutamate uptake
J Neurophysiol
Tonic release of glutamate by a DIDS-sensitive mechanism in rat hippocampal slices
J Physiol
Integrins mediate functional pre- and postsynaptic maturation at a hippocampal synapse
Nature
Synaptically released glutamate activates extrasynaptic NMDA receptors on cells in the ganglion cell layer of rat retina
J Neurosci
The chemical biology of clinically tolerated NMDA receptor antagonists
J Neurochem
Organization of the core structure of the postsynaptic density
Proc Natl Acad Sci U S A
Regulation of the NMDA receptor complex and trafficking by activity-dependent phosphorylation of the NR2B subunit PDZ ligand
J Neurosci
Activity-dependent recruitment of extrasynaptic NMDA receptor activation at an AMPA receptor-only synapse
J Neurosci
Developmental period for N-methyl-D-aspartate (NMDA) receptor-dependent synapse elimination correlated with visuotopic map refinement
J Comp Neurol
Chronic NMDA receptor blockade from birth delays the maturation of NMDA currents, but does not affect AMPA/kainate currents
J Neurophysiol
Developmental switch in the contribution of presynaptic and postsynaptic NMDA receptors to long-term depression
J Neurosci
PDZ protein interactions underlying NMDA receptor-mediated excitotoxicity and neuroprotection by PSD-95 inhibitors
J Neurosci
Role of distinct NMDA receptor subtypes at central synapses
Sci STKE
Deriving the glutamate clearance time course from transporter currents in CA1 hippocampal astrocytes: transmitter uptake gets faster during development
J Neurosci
Rapid synaptic remodeling by protein kinase C: reciprocal translocation of NMDA receptors and calcium/calmodulin-dependent kinase II
J Neurosci
A critical interaction between NR2B and MAGUK in L-DOPA induced dyskinesia
J Neurosci
Calcium-calmodulin-dependent protein kinase II phosphorylation modulates PSD-95 binding to NMDA receptors
Eur J Neurosci
Cited by (110)
Inhibition of Nwd1 activity attenuates neuronal hyperexcitability and GluN2B phosphorylation in the hippocampus
2019, EBioMedicineCitation Excerpt :Together, our findings highlight that glutamatergic synaptic transmission is downregulated by Nwd1 silencing via postsynaptic GluN2B-containing-NMDAR-mediated mechanisms. NMDAR surface proteins, especially the GluN2B subunit, are dynamic, and their trafficking, insertion, and internalization are tightly regulated [54ā56]. The tyrosine phosphorylation of NMDAR subunits is an important regulatory mechanism for plastic changes in NMDARs [57].
Fast-acting antidepressant activity of ketamine: highlights on brain serotonin, glutamate, and GABA neurotransmission in preclinical studies
2019, Pharmacology and TherapeuticsPathogenicity of Antibodies against NMDA Receptor: Molecular Insights into Autoimmune Psychosis
2018, Trends in NeurosciencesCitation Excerpt :Once inserted in the membrane, NMDARs are mobile and laterally diffuse in the plasma membrane, eventually entering a synaptic compartment where they become transiently anchored through proteināprotein interactions, for instance, with postsynaptic scaffolding proteins [16ā18]. Our understanding of this surface trafficking process emerged from the development of super-resolution and single molecule imaging approaches such as single nanoparticle (quantum dot) tracking in live neuronal networks (Figure 1A) [19,20]. Besides modulating the NMDAR synaptic pool, these fast dynamics play an instrumental role in synaptic plasticity, for instance, long-term potentiation, and in the establishment of mature synapses and during neurodevelopment and in associative memory formation [21,22].