Trends in Neurosciences
ReviewCa2+-permeable AMPA receptors in synaptic plasticity and neuronal death
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)
Divalent ion permeability of AMPA receptor channels is dominated by the edited form of a single subunit
Neuron
(1992)Relative abundance of subunit mRNAs determines gating and Ca2+ permeability of AMPA receptors in principal neurons and interneurons in rat CNS
Neuron
(1995)- et al.
Inward rectification of both AMPA and kainate subtype glutamate receptors generated by polyamine-mediated ion channel block
Neuron
(1995) RNA editing at arg607 controls AMPA receptor exit from the endoplasmic reticulum
Neuron
(2002)AMPA receptor tetramerization is mediated by Q/R editing
Neuron
(2003)Developmentally regulated, combinatorial RNA processing modulates AMPA receptor biogenesis
Neuron
(2006)Subunit composition at the single-cell level explains functional properties of a glutamate-gated channel
Neuron
(1994)Differences in Ca2+ permeability of AMPA-type glutamate receptor channels in neocortical neurons caused by differential GluR-B subunit expression
Neuron
(1994)Calcium microdomains in aspiny dendrites
Neuron
(2003)Miniature neurotransmission stabilizes synaptic function via tonic suppression of local dendritic protein synthesis
Cell
(2006)