Key Points
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Silent synapses, which cannot mediate neurotransmission because they lack functional AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors), were discovered in the hippocampal CA1 subfield amidst the debate over whether long-term potentiation (LTP) resulted from a presynaptic or a postsynaptic modification. Their existence helped to explain what had seemed to be contradictory findings regarding the locus of LTP expression.
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Silent synapses — which are found not only in the hippocampus but also in many areas of the brain and spinal cord — exhibit a developmental gradient, declining in prevalence over the first few days to weeks of life in rodents.
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Synapse unsilencing occurs when coordinated pre- and postsynaptic activity — as encountered during an LTP induction protocol — results in the activation of NMDARs (N-methyl-D-aspartate receptors) and the subsequent recruitment of AMPARs to the postsynaptic membrane. Synapse unsilencing is a mechanism of LTP expression.
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Some groups have proposed that synaptic silence may result from slow glutamate diffusion rather than from absent AMPARs. Glutamate spillover from adjacent synapses and impaired release from an immature presynaptic terminal are two models discussed.
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However, the preponderance of evidence favours the hypothesis that synaptic silence results instead from the physical absence of functional AMPARs at the postsynaptic membrane. Glutamate uncaging experiments have provided the most-direct, unequivocal evidence that LTP and synaptic silence occur by a postsynaptic mechanism.
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This characterization of silent synapses has culminated in a general acceptance that the movement of AMPARs into and out of synapses accounts for excitatory synaptic plasticity. The next challenge is to identify the molecular underpinnings of AMPAR trafficking.
Abstract
Silent synapses abound in the young brain, representing an early step in the pathway of experience-dependent synaptic development. Discovered amidst the debate over whether long-term potentiation reflects a presynaptic or a postsynaptic modification, silent synapses — which in the hippocampal CA1 subfield are characterized by the presence of NMDA receptors but not AMPA receptors — have stirred some mechanistic controversy of their own. Out of this literature has emerged a model for synapse unsilencing that highlights the central role for postsynaptic AMPA-receptor trafficking in the expression of excitatory synaptic plasticity.
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Acknowledgements
We thank A. Jackson, W. Lu, A. Milstein and A. Tzingounis for their thoughtful comments on the manuscript. R.A.N. is supported by grants from the US National Institutes of Health and G.A.K. was supported by the Larry L. Hillblom Foundation.
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Glossary
- CA1
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The area of the hippocampus that lies at the end of the hippocampal trisynaptic circuit.
- Silent synapse
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Aside from the exceptions indicated in this Review, silent synapses are synapses that exhibit an NMDA-receptor-mediated response but no AMPA-receptor-mediated response.
- Excitatory postsynaptic current
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(EPSC). The current that is recorded in a voltage-clamped neuron in response to release of synaptic glutamate.
- NMDAR
-
(N-methyl-D-aspartate receptor). The subtype of ionotropic glutamate receptor, containing the subunit NR1 complexed with some combination of the subunits NR2A–NR2D and NR3A or NR3B, that responds selectively to NMDA by gating a cationic channel that is distinguished both by its permeability to Ca2+ and by its voltage-dependent blockade by Mg2+ at the resting membrane potential.
- AMPAR
-
(α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor). The subtype of ionotropic glutamate receptor that contains a tetramer of some combination of the subunits GluR1–GluR4, responds selectively to AMPA by gating a monovalent cation current, and mediates most fast excitatory neurotransmission in the brain.
- LTP
-
(Long-term potentiation). A form of synaptic plasticity that is mostly studied in hippocampal CA1 pyramidal neurons but that is found in many other areas of the brain. It is characterized by a persistent enhancement of neurotransmission following an appropriate stimulus (see Hebb's rule).
- Pyramidal neurons
-
The principal cells of the hippocampus and the neocortex. These large cells use glutamate as their neurotransmitter.
- Paired pulse facilitation
-
The phenomenon whereby the amplitude of an EPSC that is triggered shortly (for example, 50 ms) after a prior EPSC is increased relative to that of the prior EPSC, reflecting an increased probability of presynaptic vesicle release and probably resulting from an increased presynaptic Ca2+ concentration.
- Pairing
-
Delivering low-frequency presynaptic stimulation and simultaneously depolarizing the postsynaptic cell. This triggers LTP in a manner that is consistent with Hebb's rule.
- Hebb's rule
-
(or Hebb's postulate). The notion that after a presynaptic neuron and a postsynaptic neuron fire in unison, the efficiency of neurotransmission between them improves.
- MK-801
-
An NMDAR antagonist that is use-dependent (that is, it binds inside the open channel pore only after agonist binding) and poorly reversible (that is, once it is in the pore it binds tightly with a very slow unbinding rate).
- Tetanic stimulation
-
The delivery of a rapid train of presynaptic stimuli through an extracellular stimulating electrode positioned near a bundle of axons, typically to trigger synaptic plasticity.
- Glutamate transporters
-
Transmembrane proteins that bind extracellular glutamate and transport it into astrocytes and neurons, thereby contributing to the cessation of excitatory synaptic transmission after presynaptic glutamate release.
- Cyclothiazide
-
A drug that binds AMPARs, blocking the normal fast desensitization of these receptors to glutamate.
- FM1-43
-
An ampiphilic styryl dye that reversibly partitions into lipid bilayers; after exposing neurons to this dye, inducing neuronal activity and then washing off the dye, recycled presynaptic vesicles retain a fluorescent signal, which allows visualization of presynaptic boutons under light microscopy.
- Iontophoresis
-
Ejection of a charged chemical from a high-resistance glass microelectrode through the delivery of a current pulse.
- Autapse
-
A synapse formed by a neuron onto itself, usually in the context of isolated single-neuron microisland cultures.
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Kerchner, G., Nicoll, R. Silent synapses and the emergence of a postsynaptic mechanism for LTP. Nat Rev Neurosci 9, 813–825 (2008). https://doi.org/10.1038/nrn2501
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DOI: https://doi.org/10.1038/nrn2501
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