Trends in Neurosciences
Volume 27, Issue 7, 1 July 2004, Pages 428-437
Journal home page for Trends in Neurosciences

Receptor compartmentalization and trafficking at glutamate synapses: a developmental proposal

https://doi.org/10.1016/j.tins.2004.05.010Get rights and content

Abstract

This article focuses on NMDA receptor subunit changes that occur in the forebrain and midbrain during development, namely the switch from predominance of NMDA receptors rich in NR2B subunits to that of NMDA receptors rich in NR2A subunits. We review the potential roles in brain plasticity of two membrane-associated guanylate kinases (MAGUKs), SAP102 and PSD95, which form a scaffold for the ion-passing glutamate receptors at the postsynaptic density, and we consider the known functional significance of these molecules in subunit switching. In addition, based on recent analyses of the synaptic location of glutamate receptors, activity-dependent changes in developing visual neurons, and extensive data on MAGUKs, we propose a model of glutamatergic synaptic differentiation. In this model, different NMDA receptor scaffolding and signaling complexes effect the trafficking and synaptic localization of NR2A-rich and NR2B-rich receptors, leading to tangential compartmentalization of these receptors and their movement between synaptic and extrasynaptic compartments.

Section snippets

Synaptic and extrasynaptic NMDA receptors

Molecular, immunocytochemical and functional data suggest that NR2A, NR2B and NR1 subunits exist in vivo at synaptic sites as diheteromers (e.g. NR1–NR2A or NR1–NR2B) and triheteromers (e.g. NR1–NR2A–NR2B) 1, 2, 3. However, functional extrasynaptic NMDA receptors also exist 4, 5, 6, 7, 8, 9, 10. Like synaptic NMDA receptors, extrasynaptic NMDA receptors can be activated by synaptically released glutamate 11, 12, 13. Insights into the potential importance of extrasynaptic NMDA receptors in vivo

Different MAGUKs show preferences for binding to particular NMDA receptor subunits

The hypothesis that the PSD95 family of MAGUKs compartmentalizes and controls the distribution of vertebrate ionotropic glutamate receptors was advanced in 1992 with the isolation of a 95 kDa protein from the postsynaptic density [17]. Since then, the literature on associations and possible functions of the PSD95 family of molecules has grown exponentially [3]. In addition to binding NMDA receptor heteromers via the C-terminal tails of NR2 subunits 18, 19, 20, members of the PSD95 family bind K+

NMDA receptor currents and synaptic change

Biophysical analyses of the effects of NR2 subunit changes on NMDA receptor channel function indicate that heteromers containing NR2B subunits produce channels with longer open times and longer-lasting series of opening and closing, than do heteromers containing NR2A subunits. Long-open-time channels sum to produce whole cell NMDA receptor currents with longer decay times 1, 2, 33, 34. In association with increased NR2A subunit expression, whole-cell currents driven by NMDA receptors in young

A model for regulation of synaptic plasticity by two MAGUK complexes

These analyses of glutamate receptor regulation in the colliculus and visual cortex, together with the data regarding MAGUKs, suggest that different NMDA receptor scaffolding and signaling complexes effect the trafficking and synaptic localization of NR2A-rich and NR2B-rich NMDA receptors. The data also suggest that with increased retinal activity, PSD95 is inserted into the center of the postsynaptic density and displaces the NR2B–SAP102 complexes, which were initially located at the

Acknowledgements

Work in our laboratories is supported by the National Institute of Neurological Disorders and Stroke grant R01NS3290 (to M.C-P.), the National Eye Institute grants R01EY014074 and R03EYO14420 (to M.C-P.) and The Pierre L. de Bourknecht Amyotrophic Lateral Sclerosis Research Fund (to B.Z.). We would like to thank Drs Cull-Candy and Diamond for kindly providing figures for Box 1.

References (67)

  • M.S. Grubb

    Abnormal functional organization in the dorsal lateral geniculate nucleus of mice lacking the beta2 subunit of the nicotinic acetylcholine receptor

    Neuron

    (2003)
  • T. McLaughlin

    Retinotopic map refinement requires spontaneous retinal waves during a brief critical period of development

    Neuron

    (2003)
  • J. Shi

    Activity-dependent induction of tonic calcineurin activity mediates a rapid developmental downregulation of NMDA receptor currents

    Neuron

    (2000)
  • C.J. Akerman

    Visual experience before eye-opening and the development of the retinogeniculate pathway

    Neuron

    (2002)
  • C. Chen et al.

    Developmental remodeling of the retinogeniculate synapse

    Neuron

    (2000)
  • S. Naisbitt

    Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin

    Neuron

    (1999)
  • I. Ito

    Age-dependent reduction of hippocampal LTP in mice lacking N-methyl-d-aspartate receptor epsilon 1 subunit

    Neurosci. Lett.

    (1996)
  • A. Barria et al.

    Subunit-specific NMDA receptor trafficking to synapses

    Neuron

    (2002)
  • M.M. Zeron

    Increased sensitivity to N-methyl-d-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington's disease

    Neuron

    (2002)
  • A.E. El-Husseini

    Ion channel clustering by membrane-associated guanylate kinases. Differential regulation by N-terminal lipid and metal binding motifs

    J. Biol. Chem.

    (2000)
  • R. Dingledine

    The glutamate receptor ion channels

    Pharmacol. Rev.

    (1999)
  • M. Sheng et al.

    Postsynaptic signaling and plasticity mechanisms

    Science

    (2002)
  • G. Stocca et al.

    Increased contribution of NR2A subunit to synaptic NMDA receptors in developing rat cortical neurons

    J. Physiol.

    (1998)
  • G. Rumbaugh et al.

    Distinct synaptic and extrasynaptic NMDA receptors in developing cerebellar granule neurons

    J. Neurosci.

    (1999)
  • K.R. Tovar et al.

    The incorporation of NMDA receptors with a distinct subunit composition at nascent hippocampal synapses in vitro

    J. Neurosci.

    (1999)
  • R. Sattler

    Distinct roles of synaptic and extrasynaptic NMDA receptors in excitotoxicity

    J. Neurosci.

    (2000)
  • G.E. Hardingham

    Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways

    Nat. Neurosci.

    (2002)
  • B. Li

    Differential regulation of synaptic and extra-synaptic NMDA receptors

    Nat. Neurosci.

    (2002)
  • M. Aarts

    Treatment of ischemic brain damage by perturbing NMDA receptor–PSD-95 protein interactions

    Science

    (2002)
  • D.A. Rusakov et al.

    Extrasynaptic glutamate diffusion in the hippocampus: ultrastructural constraints, uptake, and receptor activation

    J. Neurosci.

    (1998)
  • S. Chen et al.

    Synaptically released glutamate activates extrasynaptic NMDA receptors on cells in the ganglion cell layer of rat retina

    J. Neurosci.

    (2002)
  • B.A. Clark et al.

    Activity-dependent recruitment of extrasynaptic NMDA receptor activation at an AMPA receptor-only synapse

    J. Neurosci.

    (2002)
  • M. Passafaro

    Subunit-specific temporal and spatial patterns of AMPA receptor exocytosis in hippocampal neurons

    Nat. Neurosci.

    (2001)
  • Cited by (210)

    View all citing articles on Scopus
    View full text