Elsevier

Neuroscience

Volume 158, Issue 1, 12 January 2009, Pages 4-18
Neuroscience

Receptor Trafficking
Review
Surface trafficking of N-methyl-d-aspartate receptors: Physiological and pathological perspectives

https://doi.org/10.1016/j.neuroscience.2008.05.029Get rights and content

Abstract

The N-methyl-d-aspartate receptor (NMDAR) plays a crucial role in shaping the strength of synaptic connections. Over the last decades, extensive studies have defined the cellular and molecular mechanisms by which synaptic NMDARs control the maturation and plasticity of synaptic transmission, and how altered synaptic NMDAR signaling is implicated in neurodegenerative and psychiatric disorders. It is now clear that activation of synaptic or extrasynaptic NMDARs produces different signaling cascades and thus neuronal functions. Our current understanding of NMDAR surface distribution and trafficking is only emerging. Exchange of NMDARs between synaptic and extrasynaptic areas through surface diffusion is a highly dynamic and regulated process. The aim of this review is to describe the identified mechanisms that regulate surface NMDAR behaviors and discuss the impact of this new trafficking pathway on the well-established NMDAR-dependent physiological and pathophysiological processes.

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 (NR2Aā€“D), 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.

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