Regulation of Ca2+-permeable AMPA receptors: synaptic plasticity and beyond

https://doi.org/10.1016/j.conb.2006.05.012Get rights and content

AMPA-type glutamate receptors (AMPARs) mediate most fast excitatory synaptic transmission in the brain. Diversity in excitatory signalling arises, in part, from functional differences among AMPAR subtypes. Although the rapid insertion or deletion of AMPARs is recognised as important for the expression of conventional forms of long-term synaptic plasticity — triggered, for example, by Ca2+ entry through NMDA-type glutamate receptors — only recently has attention focused on novel forms of plasticity that are regulated by, or alter the expression of, Ca2+-permeable AMPARs. The dynamic regulation of these receptors is important for normal synaptic function and in disease states.

Introduction

Three main families of mammalian glutamate-gated ion channels have been identified: AMPA-(α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid), kainate- and NMDA (N-methyl-d-aspartate)-receptors. Of these, AMPARs mediate the majority of fast excitatory transmission in the central nervous system (CNS). The subunits forming AMPARs (GluR1–4 or GluRA–D; encoded by genes GRIA1-4) assemble as homo- or heterotetramers, the functional properties of which are dictated by their subunit composition and by the presence of non-pore-forming, auxiliary transmembrane AMPAR-regulatory proteins (TARPs). The mRNAs encoding each subunit type are also subject to post-transcriptional modification, in the form of alternative splicing and RNA editing, contributing further diversity to key aspects of AMPAR behaviour.

One of the most striking of the RNA editing changes affects the GluR2 subunit, resulting in a glutamine (Q) to arginine (R) switch at the ‘Q/R site’ in the pore-lining (M2) region. Editing at this site is nearly 100% efficient, profoundly altering the properties of GluR2-containing AMPARs, rendering them Ca2+-impermeable. This makes the GluR2 subunit a key determinant of AMPAR function. AMPARs that lack the GluR2 subunit are permeable to Ca2+ ions, exhibit a high single-channel conductance, and are blocked in a voltage-dependent manner by endogenous polyamines (giving rise to an inwardly rectifying current-voltage [I/V] relationship).

Although the majority of AMPARs in the CNS are GluR2-containing, and hence Ca2+-impermeable, significant expression of Ca2+-permeable AMPARs is seen in neuronal and glial cells of various brain regions. It is now becoming apparent that the regulation of these Ca2+ permeable AMPARs — their expression, assembly, trafficking and turnover — is crucial in synaptic plasticity, neuronal development and neurological disease. Here, we highlight the emerging significance of Ca2+-permeable AMPARs and consider their importance in relation to normal synaptic function, plasticity, and disease states.

Section snippets

GluR2 controls AMPAR assembly

Assembly of AMPAR tetramers proceeds as a two-step process within the endoplasmic reticulum (ER). This process involves the preferential formation of heterodimers, mediated by the luminal N-termini of the subunits [1, 2, 3], followed by the assembly of a pair of dimers [2]. The presence of a charged arginine residue at the Q/R site of GluR2 strongly influences subunit interactions during tetramerization, such that the juxtaposition of GluR2 subunits of different dimers is energetically

Ca2+ permeable AMPARs and synaptic plasticity

Until recently, our view of synaptic plasticity was based largely on studies of synapses that express mainly Ca2+-impermeable AMPARs. In the hippocampus, for example, basal AMPAR levels are maintained by constitutive AMPAR recycling involving an interaction between GluR2 and the membrane fusion protein NSF [16, 18], whereas receptor internalisation during long-term depression (LTD) is regulated by GluR2 interaction with the clathrin adaptor protein AP2 [14]. By contrast, activity-dependent

PICK, GRIP and NSF mediate changes in Ca2+-permeability

Recent studies [36••, 37••] have investigated the protein partners involved in delivery and anchoring of receptors underlying the activity-dependent plasticity of Ca2+-permeable AMPARs. When peptides that block AMPAR binding to PICK1 or NSF [16, 19] are included in the patch-pipette, there is little effect on cerebellar stellate cell miniature EPSCs (mEPSCs), whereas additionally inhibiting GRIP produces a clear rundown in amplitude [37••]. This reduction occurs only at negative potentials,

Endogenous polyamines dynamically modulate EPSCs

Intracellular polyamines confer a voltage-dependent block on Ca2+-permeable AMPARs. Initial evidence for the involvement of polyamines in synaptic plasticity came from the demonstration that tonic polyamine block of Ca2+-permeable AMPARs is transiently relieved by repetitive stimulation [40, 41] (Figure 2a). This phenomenon reduces paired-pulse depression, resulting in facilitation of synaptic responses that would normally show depression. The degree of facilitation produced depends on the

GluR2 and dendritic spines

Throughout the CNS, neurons that lack spines tend to express Ca2+-permeable AMPARs, raising the possibility that GluR2-lacking AMPARs mediate a form of Ca2+ signalling that does not require the spatial segregation normally afforded by spines. Indeed, in primary visual and somatosensory neocortex, activation of single synapses onto aspiny dendrites of fast-spiking interneurons generates Ca2+ signals that are highly restricted [48]. This ‘spine-free’ mechanism for localizing Ca2+ ‘microdomains’

Regulation of Ca2+-permeable AMPARs in disease

The dynamic properties of Ca2+-permeable AMPARs, evident in different forms of plasticity, are also relevant to various neurological conditions. Changes in the expression Ca2+-permeable AMPARs can alter synaptic properties, Ca2+-dependent signalling cascades, or lead to damage of selectively vulnerable neurons and glial cells [57, 58].

Conclusions and outlook

Far from being a relative rarity, Ca2+-permeable AMPARs are more widespread than originally thought. They are expressed in both neurons and glia, and are activated during synaptic transmission. Even though Ca2+ influx through AMPARs is modest in comparison to that through NMDARs, the location and kinetics of this influx enables it to serve distinct cellular functions. Ca2+ permeable AMPARs are exquisitely regulated in a dynamic manner through changes in subunit expression, editing and polyamine

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 are grateful to the Wellcome Trust for support, and to our colleagues for helpful discussions that have contributed to this article. SG Cull-Candy holds a Royal Society-Wolfson Research Award.

References (99)

  • N.K. Mahanty et al.

    Calcium-permeable AMPA receptors mediate long-term potentiation in interneurons in the amygdala

    Nature

    (1998)
  • J. Bischofberger et al.

    TwoB or not twoB: differential transmission at glutamatergic mossy fiber-interneuron synapses in the hippocampus

    Trends Neurosci

    (2002)
  • F. Laezza et al.

    Voltage-controlled plasticity at GluR2-deficient synapses onto hippocampal interneurons

    J Neurophysiol

    (2004)
  • S.M. Gardner et al.

    Calcium-permeable AMPA receptor plasticity is mediated by subunit-specific interactions with PICK1 and NSF

    Neuron

    (2005)
  • A. Rozov et al.

    Facilitation of currents through rat Ca2+-permeable AMPA receptor channels by activity-dependent relief from polyamine block

    J Physiol

    (1998)
  • J.J. Lawrence et al.

    Long-term specification of AMPA receptor properties after synapse formation

    J Neurosci

    (2000)
  • S.G. Sugden et al.

    Development of the specialized AMPA receptors of auditory neurons

    J Neurobiol

    (2002)
  • J.H. Goldberg et al.

    Calcium microdomains in aspiny dendrites

    Neuron

    (2003)
  • K. Toth et al.

    Afferent-specific innervation of two distinct AMPA receptor subtypes on single hippocampal interneurons

    Nat Neurosci

    (1998)
  • E.C. Fuchs et al.

    Genetically altered AMPA-type glutamate receptor kinetics in interneurons disrupt long-range synchrony of gamma oscillation

    Proc Natl Acad Sci USA

    (2001)
  • C. Matute et al.

    Glutamate-mediated glial injury: mechanisms and clinical importance

    Glia

    (2006)
  • M.R. Walters et al.

    The AMPA antagonist ZK 200775 in patients with acute ischaemic stroke: a double-blind, multicentre, placebo-controlled safety and tolerability study

    Cerebrovasc Dis

    (2005)
  • R. Kuner et al.

    Late-onset motoneuron disease caused by a functionally modified AMPA receptor subunit

    Proc Natl Acad Sci USA

    (2005)
  • Y. Kawahara et al.

    Glutamate receptors: RNA editing and death of motor neurons

    Nature

    (2004)
  • G. Zhang et al.

    Long-term alterations in glutamate receptor and transporter expression following early-life seizures are associated with increased seizure susceptibility

    J Neurochem

    (2004)
  • R. Brusa et al.

    Early-onset epilepsy and postnatal lethality associated with an editing-deficient GluR-B allele in mice

    Science

    (1995)
  • J.A. Kauer

    Learning mechanisms in addiction: synaptic plasticity in the ventral tegmental area as a result of exposure to drugs of abuse

    Annu Rev Physiol

    (2004)
  • W.A.J. Carlezon et al.

    Elevated levels of GluR1 in the midbrain: a trigger for sensitization to drugs of abuse?

    Trends Neurosci

    (2002)
  • M.J. Thomas et al.

    Long-term depression in the nucleus accumbens: a neural correlate of behavioral sensitization to cocaine

    Nat Neurosci

    (2001)
  • G.T. Swanson et al.

    Single-channel properties of recombinant AMPA receptors depend on RNA editing, splice variation, and subunit composition

    J Neurosci

    (1997)
  • J.R. Brorson et al.

    Selective expression of heteromeric AMPA receptors driven by flip-flop differences

    J Neurosci

    (2004)
  • I.H. Greger et al.

    RNA editing at arg607 controls AMPA receptor exit from the endoplasmic reticulum

    Neuron

    (2002)
  • N. Rouach et al.

    TARP gamma-8 controls hippocampal AMPA receptor number, distribution and synaptic plasticity

    Nat Neurosci

    (2005)
  • S. Tomita et al.

    Stargazin modulates AMPA receptor gating and trafficking by distinct domains

    Nature

    (2005)
  • R.A. Nicoll et al.

    Auxiliary subunits assist AMPA-type glutamate receptors

    Science

    (2006)
  • E. Kim et al.

    PDZ domain proteins of synapses

    Nat Rev Neurosci

    (2004)
  • S.H. Lee et al.

    Clathrin adaptor AP2 and NSF interact with overlapping sites of GluR2 and play distinct roles in AMPA receptor trafficking and hippocampal LTD

    Neuron

    (2002)
  • C.L. Palmer et al.

    The molecular pharmacology and cell biology of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors

    Pharmacol Rev

    (2005)
  • J. Noel et al.

    Surface expression of AMPA receptors in hippocampal neurons is regulated by an NSF-dependent mechanism

    Neuron

    (1999)
  • F. Laezza et al.

    Long-term depression in hippocampal interneurons: joint requirement for pre- and postsynaptic events

    Science

    (1999)
  • S. Lei et al.

    Distinct NMDA receptors provide differential modes of transmission at mossy fiber-interneuron synapses

    Neuron

    (2002)
  • S. Lei et al.

    Two Loci of expression for long-term depression at hippocampal mossy fiber-interneuron synapses

    J Neurosci

    (2004)
  • K. Plant et al.

    Transient incorporation of native GluR2-lacking AMPA receptors during hippocampal long-term potentiation

    Nat Neurosci

    (2006)
  • S.J. Liu et al.

    Activity-dependent change in AMPA receptor properties in cerebellar stellate cells

    J Neurosci

    (2002)
  • S.Q. Liu et al.

    Synaptic activity at calcium-permeable AMPA receptors induces a switch in receptor subtype

    Nature

    (2000)
  • S.K. Kamboj et al.

    Intracellular spermine confers rectification on rat calcium-permeable AMPA and kainate receptors

    J Physiol

    (1995)
  • X. Bai et al.

    Neuronal activity regulates protein and gene expressions of GluR2 in postnatal rat visual cortical neurons in culture

    J Neurocytol

    (2003)
  • W. Ju et al.

    Activity-dependent regulation of dendritic synthesis and trafficking of AMPA receptors

    Nat Neurosci

    (2004)
  • T.C. Thiagarajan et al.

    Adaptation to synaptic inactivity in hippocampal neurons

    Neuron

    (2005)
  • Cited by (362)

    View all citing articles on Scopus
    View full text