Dynamics of postsynaptic glutamate receptor targeting

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Targeting of glutamate receptors to synapses is an important event in both developing and mature neurons. Glutamate receptors are delivered to nascent synapses during synaptogenesis and to existing synapses during activity-dependent synaptic strengthening. Increasing evidence suggests that glutamate receptors are inserted into the plasma membrane before they accumulate at the synapse. Lateral diffusion of receptors occurs at both synaptic and non-synaptic membranes, and glutamate receptors can exchange rapidly between synaptic and extrasynaptic sites. In addition, recent studies show that postsynaptic scaffold molecules can be highly mobile. The dynamic nature of the synapse suggests that many mechanisms might be involved in regulating synapse formation and synaptic plasticity.

Introduction

Glutamate is the main excitatory neurotransmitter in the mammalian brain. Glutamate receptors are classified into two main categories: ligand-gated ion channels (ionotropic receptors) and G-protein-coupled receptors (metabotropic receptors). Among the different types of ionotropic glutamate receptor, the α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA)-type and the kainate-type receptors mediate most fast synaptic transmission in the mammalian brain, whereas the N-methyl-d-aspartate (NMDA)-type receptor mediates a slower component of synaptic transmission that is important for modulating synaptic function. Metabotropic glutamate receptors (mGluRs) are categorized into three groups on the basis of both their pharmacological profiles and the second messenger systems to which they are coupled. Group I mGluRs (mGluR1 and mGluR5) are predominantly localized at the postsynaptic sites, whereas others mGluRs function at presynaptic sites.

Ionotropic glutamate receptors are primarily targeted to neuronal dendrites, although increasing evidence suggests that all three types of ionotropic glutamate receptor can be targeted to presynaptic membranes in a neuron-specific and sometimes subunit-specific manner [1, 2, 3, 4, 5, 6]. Like many proteins, glutamate receptors are synthesized in the endoplasmic reticulum and transported to the Golgi apparatus. Neurons are highly polarized cells in which proteins are sorted and transported to their target locations after exiting from the Golgi. Many pathways and mechanisms are involved in synaptic targeting of glutamate receptors.

In this review, we focus mainly on targeting of glutamate receptors to neuronal dendrites, summarizing recent findings on receptor dynamics related to the surface and synaptic localization of these receptors.

Section snippets

Vesicular trafficking versus lateral diffusion in dendrites

Several mechanisms, such as microtubule-based vesicular transport and lateral diffusion in the plasma membrane, might be involved in localizing glutamate receptors to dendritic membranes (Figure 1).

Vesicles containing NMDA receptors (NMDARs) are associated with microtubules in dendrites, and a specific kinesin motor KIF17 is required for trafficking NMDAR-containing vesicles [7, 8]. Mobile NMDARs are also present at the plasma membrane [9, 10], however, suggesting that lateral diffusion in the

Lateral movement into and out of synapses

Glutamate receptors in dendritically sorted vesicles are inserted into the cytoplasmic membrane, most probably at extrasynaptic sites because of the spatial obstruction presented by the dense protein network in the postsynaptic density (Figure 1). A two-step trafficking model for AMPARs, involving membrane insertion followed by synaptic recruitment, has been proposed by a study of Stargazin-deficient neurons [45]. Evidence supporting the notion that extrasynaptic receptors act as a reservoir

Fast incorporation of locally translated glutamate receptors

Since the initial observation of protein synthetic machinery in neuronal dendrites [58], local translation of protein has emerged as an attractive mechanism that contributes both to synaptogenesis and to long-lasting changes in synaptic efficacy (recently reviewed in [59, 60]). Glutamate receptor mRNAs are sorted to dendrites, and this sorting might be regulated by changes in synaptic activity [61, 62••]. Exciting progress has been made in recent years in understanding activity-dependent

Conclusions

Synaptic incorporation of glutamate receptors is one of the most important steps in synaptogenesis. The conventional view that the AMPAR is the most dynamic component of the excitatory synapse has been challenged by recent observations of equally dynamic movements of NMDARs and mGluRs into and out of synapses. In addition to regulating receptor trafficking, both synaptic activity and the cytoskeleton network influence the rapid turnover and lateral movement of postsynaptic scaffolds at active

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank Roger Nicoll and members of the Chen laboratory for discussions and comments on the manuscript. LC is supported by grants from the Arnold and Mabel Beckman Foundation, the David and Lucile Packard Foundation, the WM Keck Foundation, National Alliance for Research on Schizephrenia and Depression (NARSAD) and the National Institute of Mental Health (NIMH).

References (68)

  • P. Sah et al.

    Tonic activation of NMDA receptors by ambient glutamate enhances excitability of neurons

    Science

    (1989)
  • C.M. Niell et al.

    In vivo imaging of synapse formation on a growing dendritic arbor

    Nat Neurosci

    (2004)
  • P. Thomas et al.

    Dynamic mobility of functional GABAA receptors at inhibitory synapses

    Nat Neurosci

    (2005)
  • K.C. Martin et al.

    RNA trafficking and local protein synthesis in dendrites: an overview

    J Neurosci

    (2006)
  • T.C. Thiagarajan et al.

    Adaptation to synaptic inactivity in hippocampal neurons

    Neuron

    (2005)
  • C. Hanus et al.

    Activity-dependent movements of postsynaptic scaffolds at inhibitory synapses

    J Neurosci

    (2006)
  • R. Fabian-Fine et al.

    Age-dependent pre- and postsynaptic distribution of AMPA receptors at synapses in CA3 stratum radiatum of hippocampal slice cultures compared with intact brain

    Eur J Neurosci

    (2000)
  • R. Chittajallu et al.

    Regulation of glutamate release by presynaptic kainate receptors in the hippocampus

    Nature

    (1996)
  • M. Casado et al.

    Presynaptic N-methyl-d-aspartate receptors at the parallel fiber–Purkinje cell synapse

    Proc Natl Acad Sci USA

    (2000)
  • S. Satake et al.

    Synaptic activation of AMPA receptors inhibits GABA release from cerebellar interneurons

    Nat Neurosci

    (2000)
  • M. Setou et al.

    Kinesin superfamily motor protein KIF17 and mLin-10 in NMDA receptor-containing vesicle transport

    Science

    (2000)
  • P. Washbourne et al.

    Cycling of NMDA receptors during trafficking in neurons before synapse formation

    J Neurosci

    (2004)
  • J.R. Cottrell et al.

    Distribution, density, and clustering of functional glutamate receptors before and after synaptogenesis in hippocampal neurons

    J Neurophysiol

    (2000)
  • L. Groc et al.

    Differential activity-dependent regulation of the lateral mobilities of AMPA and NMDA receptors

    Nat Neurosci

    (2004)
  • L. Shen et al.

    Regulation of AMPA receptor GluR1 subunit surface expression by a 4.1N-linked actin cytoskeletal association

    J Neurosci

    (2000)
  • A.J. Borgdorff et al.

    Regulation of AMPA receptor lateral movements

    Nature

    (2002)
  • C. Tardin et al.

    Direct imaging of lateral movements of AMPA receptors inside synapses

    EMBO J

    (2003)
  • Y. Sekine-Aizawa et al.

    Imaging of receptor trafficking by using α-bungarotoxin-binding-site-tagged receptors

    Proc Natl Acad Sci USA

    (2004)
  • M. Passafaro et al.

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

    Nat Neurosci

    (2001)
  • J.W. Lin et al.

    Distinct molecular mechanisms and divergent endocytotic pathways of AMPA receptor internalization

    Nat Neurosci

    (2000)
  • S.P. Gross

    Hither and yon: a review of bi-directional microtubule-based transport

    Phys Biol

    (2004)
  • T. Biederer et al.

    SynCAM, a synaptic adhesion molecule that drives synapse assembly

    Science

    (2002)
  • P. Scheiffele et al.

    Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons

    Cell

    (2000)
  • E.R. Graf et al.

    Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins

    Cell

    (2004)
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