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NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders

Lau, C. Geoffrey, Zukin, R. Suzanne·2007·Nature Reviews Neuroscience

DOI 10.1038/nrn2153

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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.

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“Knockdown of NR1 mRNA in the DRG may further decrease the expression of NMDA receptors on primary afferent axons, as the functional NMDA receptors are transported in and out of the cell membrane dynamically to regulate the transmission efficacy and remodel synapses (Lau & Zukin, 2007).”
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“Findings from such studies could enable the production of improved treatments for developmental and adult disorders where NMDARs are implicated, including Fragile X syndrome, autism spectrum disorders, and schizophrenia (Lau and Zukin 2007).”
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“The phosphorylated PKA further activates MAPK and promotes it to enter the nucleus to phosphorylate cAMP response element binding protein (CREB1), then initiates transcription program, leading to the formation of new synaptic structures.([27]) Additionally, the continuous Ca/calmodulin signal activates protein kinase…”
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“This indicates that synaptic NMDARs switch from a GluN2B-dominant type to a GluN2A-dominant type in response to neuronal activity and sensory experiences during development (Lau and Zukin, 2007).”
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“The composition of subunits varies across different regions of the CNS, during development, and along disease states [10,12,13].”
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“Dysregulation of NMDA receptor activity has been implicated in age-related cognitive decline as well as AD [74].”
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“higher-order brain functions [5, 6], whereas aberrant NMDAR functions are implicated in a wide range of psychiatric and neurological disorders [1, 2, 7].”
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“Because glutamate and its ionotropic Nmethyl-D-aspartate (NMDA) receptors have been known to be associated with synaptic plasticity, glutamate and NMDA receptorsmediated signaling have become targets of interest in exploring the pharmacological treatment of ASDs [3,4].”
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“In support of this hypothesis, the functional NMDA receptors assembled in the endoplasmic reticulum have been found to be transported in and out of cell membrane dynamically for the regulation of synaptic efficacy and remodeling [18].”
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Authors: Lau, C. G., & Zukin, R. S.
Affiliations: Albert Einstein College of Medicine (US)
Corresponding author: Zukin, R. Suzanne
ORCID: Lau, C. Geoffrey
Zukin, R. Suzanne
Venue: Nature Reviews Neuroscience
Publisher: Springer Science and Business Media LLC
Published: 2007-06
Volume: 8
Issue: 6
Pages: 413-426
ISSN: 1471-003X (ISSN-L)
1471-0048
DOI: 10.1038/nrn2153
OpenAlex: W1985241009
Cited by: 1,159
References: 154
Citations by year: 2026: 27 · 2025: 27 · 2024: 35 · 2023: 50 · 2022: 39 · 2021: 60 · 2020: 54 · 2019: 70 · 2018: 75 · 2017: 66 · 2016: 51 · 2015: 78 · 2014: 70 · 2013: 69 · 2012: 89
FWCI: 6.05
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature reviews. Neuroscience (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Institute of Neurological Disorders and Stroke (NS-20752, R01NS020752)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Keywords: NMDA receptor, receptor trafficking, synaptic plasticity, postsynaptic density, receptor subunit composition, synaptic targeting, endolysosomal pathway, extrasynaptic receptors, activity-dependent regulation, cocaine dependence, Alzheimer's disease, schizophrenia, neuropsychiatric disorders
MeSH terms: Animals, Mental Disorders, Brain, Endocytosis, Humans, Synaptic Transmission, Neuronal Plasticity, Synapses, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Protein Transport

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NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders

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