Review
Ca2+-permeable AMPA receptors in synaptic plasticity and neuronal death

https://doi.org/10.1016/j.tins.2007.01.006Get rights and content

AMPA receptors mediate fast synaptic transmission at excitatory synapses in the CNS and are crucial during neuronal development, synaptic plasticity and structural remodeling. AMPA receptors lacking GluR2 subunits are permeable to Ca2+ and Zn2+. Ca2+ permeation through AMPA receptors is crucial in several forms of synaptic plasticity and cell death associated with neurological diseases and disorders. The subunit composition and Ca2+ permeability of AMPA receptors are not static, but they are dynamically remodeled in a cell- and synapse-specific manner during development and in response to neuronal activity, sensory experience and neuronal insults. Exciting new research shows that these changes arise not only because of regulated expression of the AMPA receptor subunit GluR2, but also as a consequence of RNA editing, receptor trafficking and dendritic protein synthesis. This article reviews new insights into the role of Ca2+-permeable AMPA receptors in neuronal function and survival.

Introduction

AMPA receptors mediate fast synaptic transmission at excitatory synapses in the CNS and are crucial during neuronal development, synaptic plasticity and structural remodeling. AMPA receptors are tetrameric assemblies of subunits GluR1–4 (or subunits GluRA–D), which are encoded by separate genes and differentially expressed throughout the CNS (reviewed in [1]). Additional molecular diversity arises through RNA editing (Box 1) and alternative splicing. Each AMPA receptor subunit contains a large extracellular N-terminal domain, three membrane-spanning domains, a re-entry or hairpin loop that forms the pore-lining region (membrane domain 2) and an intracellular C-terminal domain. AMPA receptors lacking GluR2 are permeable to Ca2+ and Zn2+ 2, 3, 4, 5 and exhibit distinctly fast kinetics [4] and a characteristic inwardly rectifying current–voltage (I–V) relation, owing to voltage-dependent block by intracellular polyamines 6, 7, 8, 9 (Figure 1). Owing largely to a crucial arginine (R) residue in its pore-lining membrane domain 2, the presence of GluR2 in heteromeric AMPA receptors renders the channel impermeable to Ca2+ and Zn2+ and electrically linear (Figure 1). The presence of GluR2 also influences channel kinetics [4], conductance [10], AMPA receptor assembly, forward trafficking from the endoplasmic reticulum (ER) and targeting to and from synaptic sites 11, 12, 13, 14 (Box 2). Thus, even a modest alteration in the level of expression of GluR2 is expected to have profound implications for synaptic efficacy and neuronal survival.

Most principal neurons of the neocortex, hippocampus, amygdala and cerebellum express GluR2-containing, Ca2+-impermeable AMPA receptors 4, 15, 16, 17. In these cells, the acute loss of GluR2 confers selective vulnerability to neuronal insults (see below). By contrast, aspiny neurons throughout the CNS, including neocortical, hippocampal and amygdaloid fast-spiking interneurons, cerebellar stellate cells, dorsal horn interneurons, large striatal cholinergic interneurons, bushy and stellate cells of the cochlear nucleus, spinothalamic projection neurons and retinal AII amacrine cells, in addition to Bergmann glia and oligodendrocyte precursor cells of the cerebellum, express GluR2-lacking, Ca2+-permeable AMPA receptors [18]. In these cells, AMPA receptor-mediated Ca2+ signaling is rapid and compartmentalized, owing mainly to fast, local Ca2+-extrusion pumps, and crucial for synaptic plasticity. The rapid response kinetics of GluR2-lacking AMPA receptors is also thought to be instrumental in synchronous firing of neocortical layer 2 and 3 interneurons during fast brain waves or gamma oscillations involved in transmission of information to distant regions of the brain [19]. The subunit composition and electrical properties of AMPA receptors also vary in a synapse-specific manner within individual neurons 20, 21. This feature enables individual neurons to produce different responses to distinct afferent inputs and might be important to information processing and integration within neural circuits.

The subunit composition and Ca2+ permeability of AMPA receptors are not static, but they are dynamically remodeled in a cell- and synapse-specific manner during development and in response to neuronal activity. Recent studies show that these changes arise not only as a consequence of redistribution or trafficking of AMPA receptor subunits, but also owing to activity-dependent local protein synthesis of AMPA receptors in dendrites 22, 23. The subunit composition and Ca2+ permeability of AMPA receptors are also remodeled by neuronal insults (e.g. seizures) 24, 25, 26, ischemic insults 27, 28, 29, 30, 31, excitotoxicity 32, 33, spinal cord injury [34], antipsychotics [35], drugs of abuse [36], corticosteroids [37] and neurological diseases [e.g. Alzheimer's disease [38] and amyotrophic lateral sclerosis (ALS)] 39, 40. These changes arise not only owing to dysregulation of the expression of GluR2, but also because of RNA editing 41, 42 and receptor trafficking [43]. This article reviews new insights into the molecular mechanisms underlying activity-dependent remodeling of the subunit composition and permeability of synaptic AMPA receptors and highlights the importance of Ca2+-permeable AMPA receptors in synaptic plasticity and neuronal death.

Section snippets

Ca2+-permeable AMPA receptors in synaptic plasticity

AMPA receptor-mediated Ca2+ influx can influence synaptic efficacy in at least two ways. First, Ca2+ influx can activate intracellular signaling cascades, which regulate AMPA receptor trafficking, local translation and/or gene transcription, and thereby effect long-term changes in synapse performance. Second, Ca2+ influx can induce a switch in synaptic AMPA receptor subtype, thereby altering the qualitative properties (permeability, kinetics and electrical rectification) of the synapse. A

GluR2-lacking AMPA receptors in ischemia

Ca2+-permeable AMPA receptors have a crucial role not only in synaptic plasticity, but also in the excitotoxicity associated with several neurological disorders and diseases. Transient global or forebrain ischemia arising as a consequence of cardiac arrest or induced experimentally in animals causes selective, delayed neuronal death, primarily of hippocampal CA1 pyramidal neurons, and marked cognitive deficits. A striking feature is an early rise in intracellular Ca2+ during the ischemic

Concluding remarks

The past few years have witnessed an explosion of new information concerning the role of Ca2+-permeable AMPA receptors in synaptic plasticity and neuronal death. Exciting new research has revealed novel mechanisms by which the subunit composition and Ca2+ permeability of AMPA receptors are modified in response to neuronal activity, sensory experience and neuronal insults. Unlike activity-dependent modifications in the number of synaptic AMPA receptors, activity-dependent modifications in the

Acknowledgements

This work was supported by generous grants from the F.M. Kirby Foundation (R.S.Z.), National Institutes of Health Grant NS46742 (R.S.Z.) and National Science Foundation IBN-0344559 (S.Q.J.L.).

References (86)

  • P.H. Seeburg et al.

    Regulation of ion channel/neurotransmitter receptor function by RNA editing

    Curr. Opin. Neurobiol.

    (2003)
  • S. Kwak et al.

    Calcium-permeable AMPA channels in neurodegenerative disease and ischemia

    Curr. Opin. Neurobiol.

    (2006)
  • B. Hartmann

    The AMPA receptor subunits GluR-A and GluR-B reciprocally modulate spinal synaptic plasticity and inflammatory pain

    Neuron

    (2004)
  • G.J. Quirk

    Fear conditioning enhances short-latency auditory responses of lateral amygdala neurons: parallel recordings in the freely behaving rat

    Neuron

    (1995)
  • S.M. Gardner

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

    Neuron

    (2005)
  • T.C. Thiagarajan

    Adaptation to synaptic inactivity in hippocampal neurons

    Neuron

    (2005)
  • R.L. Clem et al.

    Pathway-specific trafficking of native AMPARs by in vivo experience

    Neuron

    (2006)
  • S. Liu

    Expression of Ca2+-permeable AMPA receptor channels primes cell death in transient forebrain ischemia

    Neuron

    (2004)
  • P.L. Peng

    ADAR2-dependent RNA editing of AMPA receptor subunit GluR2 determines vulnerability of neurons in forebrain ischemia

    Neuron

    (2006)
  • D.E. Pellegrini-Giampietro

    The GluR2 (GluR-B) hypothesis: Ca2+-permeable AMPA receptors in neurological disorders

    Trends Neurosci.

    (1997)
  • M. Higuchi

    RNA editing of AMPA receptor subunit GluR-B: a base-paired intron–exon structure determines position and efficiency

    Cell

    (1993)
  • B. Sommer

    RNA editing in brain controls a determinant of ion flow in glutamate-gated channels

    Cell

    (1991)
  • S. Shi

    Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons

    Cell

    (2001)
  • M.F. Barry et al.

    Receptor trafficking and the plasticity of excitatory synapses

    Curr. Opin. Neurobiol.

    (2002)
  • I. Song et al.

    Regulation of AMPA receptors during synaptic plasticity

    Trends Neurosci.

    (2002)
  • N. Ballas et al.

    The many faces of REST oversee epigenetic programming of neuronal genes

    Curr. Opin. Neurobiol.

    (2005)
  • N. Ballas

    Regulation of neuronal traits by a novel transcriptional complex

    Neuron

    (2001)
  • N. Ballas

    REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis

    Cell

    (2005)
  • R. Dingledine

    The glutamate receptor ion channels

    Pharmacol. Rev.

    (1999)
  • M. Hollmann

    Ca2+ permeability of KA–AMPA-gated glutamate receptor channels depends on subunit composition

    Science

    (1991)
  • T.A. Verdoorn

    Structural determinants of ion flow through recombinant glutamate receptor channels

    Science

    (1991)
  • S.D. Donevan et al.

    Intracellular polyamines mediate inward rectification of Ca2+- permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors

    Proc. Natl. Acad. Sci. U. S. A.

    (1995)
  • S.K. Kamboj

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

    J. Physiol.

    (1995)
  • D.S. Koh

    Block of native Ca2+-permeable AMPA receptors in rat brain by intracellular polyamines generates double rectification

    J. Physiol.

    (1995)
  • G.T. Swanson

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

    J. Neurosci.

    (1997)
  • M. Passafaro

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

    Nat. Neurosci.

    (2001)
  • B. Lambolez

    Correlation between kinetics and RNA splicing of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors in neocortical neurons

    Proc. Natl. Acad. Sci. U. S. A.

    (1996)
  • E.C. Fuchs

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

    Proc. Natl. Acad. Sci. U. S. A.

    (2001)
  • S.M. Gardner

    Correlation of AMPA receptor subunit composition with synaptic input in the mammalian cochlear nuclei

    J. Neurosci.

    (2001)
  • K. Toth et al.

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

    Nat. Neurosci.

    (1998)
  • S.Y. Grooms

    Activity bidirectionally regulates AMPA receptor mRNA abundance in dendrites of hippocampal neurons

    J. Neurosci.

    (2006)
  • L.K. Friedman

    Kainate-induced status epilepticus alters glutamate and GABAA receptor gene expression in adult rat hippocampus: an in situ hybridization study

    J. Neurosci.

    (1994)
  • S.Y. Grooms

    Status epilepticus decreases glutamate receptor 2 mRNA and protein expression in hippocampal pyramidal cells before neuronal death

    Proc. Natl. Acad. Sci. U. S. A.

    (2000)
  • Cited by (0)

    View full text