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NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders

Key Points

  • Synaptic NMDARs (N-methyl-D-aspartate receptors) and AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors), two major classes of glutamate-gated ion channels, are localized to postsynaptic densities (PSDs) where they are structurally organized (and spatially restricted) in a large macromolecular signalling complex of scaffolding and adaptor proteins, which physically links the receptors to kinases, phosphatases and other downstream signalling proteins.

  • NMDARs are synthesized and co-translationally assemble in the endoplasmic reticulum (ER) to form functional channels with differing physiological and pharmacological properties and distinct patterns of synaptic targeting. Nascent NMDARs are transported in vesicles with adaptor and scaffolding proteins by the kinesin motor KIF17 along microtubules in dendrites to synaptic sites.

  • New research provides evidence that synaptic NMDAR number and subunit composition are not static, but change dynamically in a cell- and synapse-specific manner during development and in response to neuronal activity and sensory experience. Activity drives not only NMDAR synaptic targeting and incorporation, but also receptor retrieval, differential sorting of receptors into the endosomal–lysosomal pathway and lateral diffusion between synaptic and extrasynaptic sites.

  • Homeostatic mechanisms limit NMDAR synaptic strength by regulating receptor number and phenotype at synaptic sites. Whereas activity blockade promotes alternative RNA splicing of the NR1 subunit and accelerates forward trafficking of NMDARs, chronic neuronal activity drives subunit-specific receptor internalization, intracellular sorting and protein degradation via the ubiquitin–proteasome system.

  • Emerging evidence indicates that activity-dependent insertion and retrieval of NMDARs to and from synaptic sites mediates some forms of long-term potentiation (LTP) and long-term depression (LTD), cellular processes that are widely believed to be involved in learning and memory, as well as metaplasticity at central synapses.

  • Dysregulation of NMDAR trafficking may have a role in the behavioural symptoms associated with neuropsychiatric disorders such as cocaine addiction, chronic alcohol abuse, schizophrenia and Alzheimer's disease.

Abstract

The number and subunit composition of synaptic N-methyl-D-aspartate receptors (NMDARs) are not static, but change in a cell- and synapse-specific manner during development and in response to neuronal activity and sensory experience. Neuronal activity drives not only NMDAR synaptic targeting and incorporation, but also receptor retrieval, differential sorting into the endosomal–lysosomal pathway and lateral diffusion between synaptic and extrasynaptic sites. An emerging concept is that activity-dependent, bidirectional regulation of NMDAR trafficking provides a dynamic and potentially powerful mechanism for the regulation of synaptic efficacy and remodelling, which, if dysregulated, can contribute to neuropsychiatric disorders such as cocaine addiction, Alzheimer's disease and schizophrenia.

Figure 1: The NMDAR macromolecular signalling complex at excitatory synapses.
Figure 2: NMDAR assembly and transport to dendritic spines.
Figure 3: Synaptic activity regulates the molecular composition of the postsynaptic density.
Figure 4: NMDAR subunit targeting signals.
Figure 5: Long-term potentiation and long-term depression involve activity-dependent insertion or internalization of NMDARs.
Figure 6: Dysregulation of NMDAR trafficking in neuropsychiatric disorders.

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Acknowledgements

The authors thank D. P. Purpura, M. V. L. Bennett, A. Z. Harris, B. D. Heifets, Y. R. Chin and members of the Zukin laboratory for reading earlier versions of the manuscript. Work supported by National Institutes of Health grant NS20752 to R.S.Z.

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Correspondence to R. Suzanne Zukin.

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C. Geoffrey Lau and R. Suzanne Zukin

NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nature Reviews Neuroscience 8, 413-426 (2007); doi:10.1038/nrn2153

R. Suzanne Zukin declares that she is the recipient of a small research grant from the Novo Nordisk A/S.

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Glossary

Long-term potentiation

(LTP). Activity-dependent strengthening of synaptic transmission that is long-lasting (usually more than one hour). Commonly induced by brief, high-frequency stimulation, LTP is widely believed to be a key cellular mechanism involved in learning and memory.

Long-term depression

(LTD). A long-lasting suppression of synaptic strength that is elicited by specific patterns of synaptic stimulation (for example, low-frequency stimulation). LTD is typically dependent on NMDA-receptor activation, and is widely believed to be a means of information storage in the brain.

Open probability

The fraction of time that a single channel remains open when fully activated by ligand or voltage.

Postsynaptic density

(PSD). An electron-dense specialization of excitatory postsynaptic membranes that contains a high concentration of glutamate receptors, ion channels, kinases, phosphatases and associated signalling and cytoskeletal proteins.

Ubiquitin–proteasome system

Ubiquitin is a 76 amino-acid protein that serves as a tag to mark proteins destined for degradation. Proteins tagged by a polyubiquitin chain are targeted to the proteasome, a large, multimeric barrel-like complex that acts by proteolysis to degrade proteins.

Exocyst complex

A macromolecular multimeric protein complex involved in directing cargo-loaded vesicles to sites of fusion in the plasma membrane; it is often concentrated at sites of active secretion and cell growth.

Plus-end-directed motor

Plus-end-directed motors transport cargo from the minus to the plus end of microtubules (in the anterograde direction, or from the neuronal cell body out into the neuronal process).

Extrasynaptic receptors

A receptor population located in a region of the dendritic or somatic membrane outside of the postsynaptic density and that is not activated by a single pulse of neurotransmitter release.

Excitatory postsynaptic potentials

(EPSPs). A transient postsynaptic membrane depolarization caused by presynaptic release of neurotransmitter.

PDZ domain

A modular protein interaction domain that is specialized for binding to carboxy-terminal peptide motifs of other proteins. Scaffolding and adaptor proteins that contain PDZ-domains mediate the assembly of large molecular complexes at specific subcellular sites, such as synapses. PDZ domains are named after the proteins in which these sequence motifs were originally identified (PSD-95, discs large, zona occludens 1).

Clathrin-mediated

A form of receptor-mediated endocytosis, in which invagination of the endocytic vesicle is driven by the clathrin coat.

Autaptic cultures

Cultures in which hippocampal neurons are plated at an exceedingly sparse density so that each cell is physically isolated from other cells and makes synaptic connections only with itself.

Schaffer collateral–CA1 synapse

(Sch–CA1 synapse). Synapses formed by excitatory afferents from the CA3 to CA1 pyramidal cells in the hippocampus. LTP at this synapse is one of the most well-characterized forms of synaptic plasticity in the brain.

Metaplasticity

A higher-order plasticity than synaptic plasticity, metaplasticity ('plasticity of plasticity') refers to the phenomenon whereby previous synaptic activity (for example, prolonged changes in overall network activity over long time periods) or other external stimuli can influence (the occurrence of) subsequent synaptic plasticity (process or event).

Ocular dominance columns

In the mature primary visual cortex of mammals, most neurons respond predominantly to visual inputs from one eye or the other. Ocular dominance columns arise from the spatially organized, alternating columns of cells that receive sensory information from one eye or the other.

Orientation selectivity

Property of visual cortex neurons that enables the detection of bars and edges within visual images and the encoding of their orientations. As the cortex is organized in columns, neurons that belong to the same column share the same orientation tuning.

Barrel

A cylindrical column of neurons found in the rodent neocortex. Each barrel receives sensory input from a single whisker follicle, and the topographical organization of the barrels corresponds precisely to the arrangement of whisker follicles on the face.

Silent synapse

An excitatory synapse containing functional NMDARs (N-methyl-D-aspartate receptors) but lacking AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). At the resting potential of the cell, NMDARs are blocked by extracellular Mg2+. To activate NMDARs, synaptically released glutamate must activate AMPARs, leading to Na+ influx and depolarization of the neuronal membrane, which in turn relieves block of NMDARs by Mg2+. The proportion of silent synapses at central synapses decreases during mammalian postnatal development.

Coatomer protein complex II

(COPII). The coat protein COPII forms carrier vesicles that mediate intracellular transport of newly synthesized proteins from exit sites of the endoplasmic reticulum to the cis face of the Golgi apparatus.

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Lau, C., Zukin, R. NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nat Rev Neurosci 8, 413–426 (2007). https://doi.org/10.1038/nrn2153

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