Developmental decrease in NMDA receptor desensitization associated with shift to synapse and interaction with postsynaptic density-95

Li, B., Otsu, Y., Murphy, T. H., Raymond, L. A. (December 2003) Developmental decrease in NMDA receptor desensitization associated with shift to synapse and interaction with postsynaptic density-95. Journal of Neuroscience, 23 (35). pp. 11244-54. ISSN 0270-6474

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NMDA receptors (NMDARs) play a crucial role in neuronal development, synaptic plasticity, and excitotoxicity; therefore, regulation of NMDAR function is important in both physiological and pathological conditions. Previous studies indicate that the NMDAR-mediated synaptic current decay rate increases during development because of a switch in receptor subunit composition, contributing to developmental changes in plasticity. To test whether NMDAR desensitization also changes during development, we recorded whole-cell NMDA-evoked currents in cultured rat hippocampal neurons. We found that glycine-independent desensitization of NMDARs decreases during development. This decrease was not dependent on a switch in subunit composition or differential receptor sensitivity to agonist-, Ca2+-, or Zn2+-induced increase in desensitization. Instead, several lines of evidence indicated that the developmental decrease in desensitization was tightly correlated with synaptic localization of the receptor, suggesting that association of NMDARs with proteins selectively expressed at synapses in mature neurons might account for developmental alterations in desensitization. Accordingly, we tested the role of interactions between PSD-95 (postsynaptic density-95) and NMDARs in regulating receptor desensitization. Overexpression of PSD-95 reduced NMDAR desensitization in immature neurons, whereas agents that interfere with synaptic targeting of PSD-95, or induce movement of NMDARs away from synapses and uncouple the receptor from PSD-95, increased NMDAR desensitization in mature neurons. We conclude that synaptic localization and association with PSD-95 increases stability of hippocampal neuronal NMDAR responses to sustained agonist exposure. Our results elucidate an additional mechanism for differentially regulating NMDAR function in neurons of different developmental stages or the response of subpopulations of NMDARs in a single neuron.

Item Type: Paper
Uncontrolled Keywords: Animals Cells, Cultured Chelating Agents/pharmacology Enzyme Inhibitors/pharmacology Excitatory Amino Acid Agonists/pharmacology Excitatory Amino Acid Antagonists/pharmacology Hippocampus/cytology Humans Intracellular Signaling Peptides and Proteins Kidney/cytology/drug effects/metabolism Membrane Proteins Nerve Tissue Proteins/genetics/*metabolism Neurons/cytology/drug effects/*metabolism Patch-Clamp Techniques Phosphoprotein Phosphatases/antagonists & inhibitors/metabolism Protein Kinase Inhibitors Protein Kinases/metabolism Protein Subunits/agonists/genetics/metabolism Pyramidal Cells/cytology/drug effects/metabolism Rats Receptors, N-Methyl-D-Aspartate/drug effects/genetics/*metabolism Synapses/*metabolism Time Factors Transfection
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > NMDA receptor
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > PSD95
organs, tissues, organelles, cell types and functions > sub-cellular tissues: types and functions > synapse
CSHL Authors:
Communities: CSHL labs > Li lab
Depositing User: Matt Covey
Date: 3 December 2003
Date Deposited: 12 Dec 2014 16:11
Last Modified: 12 Dec 2014 16:11
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