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REVIEWS SHORT-TERM SYNAPTIC PLASTICITY: A COMPARISON OF TWO SYNAPSES Dawn M. Blitz, Kelly A. Foster and Wade G. Regehr During physiological patterns of activity, synaptic activity is regulated by many forms of shortterm plasticity. Here, we compare the functional consequences of such plasticity at the synapse from the climbing fibre to the Purkinje cell in the cerebellum and at the synapse between the retinal ganglion cell and the thalamocortical relay neuron in the lateral geniculate nucleus. Despite superficial similarities between these two powerful synapses, they have distinctive synaptic plasticity. The climbing fibre synapse is highly reliable but accomplishes this through many synaptic specializations. However, the retinogeniculate synapse dynamically regulates the flow of visual information by using two types of receptor that have different types of plasticity. These synapses illustrate the important functional consequences of synaptic plasticity. READILY RELEASABLE POOL A pool of synaptic vesicles that is available for rapid fusion with the presynaptic membrane on arrival of a nerve impulse. The vesicles are docked to the membrane and have been biochemically primed for release. Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA. Correspondence to W.G.R. e-mail: wade_regehr@ hms.harvard.edu doi:10.1038/nrn1475 630 Although synapses throughout the brain share many features, they also have distinct properties. In most cases the same general sequence of events leads to neurotransmitter release: an action potential is initiated in the axon near the cell body, it propagates down the axon, voltage-gated calcium channels in the presynaptic terminal open and admit calcium, and this triggers vesicle fusion. Liberated neurotransmitter then binds to receptors on the postsynaptic cell and ultimately this influences the firing of the postsynaptic neuron1,2. This complex series of events is regulated in many ways, which makes each type of synapse distinct. Synapses can differ in size, probability of transmitter release and complement of postsynaptic receptors3–6. In addition, physiological activity patterns, in which synaptic inputs are often activated at high frequencies, sometimes in bursts, lead to alterations in synaptic strength at all types of synapse7–11. How the spiking pattern of a presynaptic cell ultimately influences the firing of its targets depends on the properties of short-term plasticity that are specific to the activated synapses7,12–14. Many mechanisms can lead to use-dependent alterations in synaptic strength during high-frequency activation15,16. At some synapses, a reduction in neurotransmitter release leads to short-term depression either by reducing the probability of release or by depleting the | AUGUST 2004 | VOLUME 5 of vesicles17,18 (FIG. 1a). At other synapses, repeated activation increases the probability of neurotransmitter release19, either by saturating a local calcium buffer20,21 or by increasing calcium concentration in the presynaptic terminal22–24 (FIG. 1b). The properties of postsynaptic receptors can also contribute to short-term plasticity. Desensitization of postsynaptic receptors, in which exposure to neurotransmitter results in receptors entering a non-responsive state, can reduce synaptic responses during repeated activation9,25–28 (FIG. 1c). In addition, repetitive activity can lead to a decrease in synaptic response amplitude owing to receptor saturation29–31. Receptor saturation means that fewer receptors are available for neurotransmitter to bind to on subsequent stimulation (FIG. 1d). However, currents mediated by channels with slow kinetics, such as NMDA (N-methyl-D-aspartate) channels, can still be large despite receptor saturation. This is due to summation of excitatory postsynaptic currents (EPSCs) (FIG. 1d), as occurs at the retinogeniculate synapse (see below)9. Saturation of receptor/channel complexes with faster kinetics, such as AMPA (α-amino3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors, can have quite different consequences, as found at the synapse between the climbing fibre and the Purkinje cell (see below)30. This is only a partial list of READILY RELEASABLE POOL www.nature.com/reviews/neuro ©2004 Nature Publishing Group REVIEWS Similarities of two powerful synapses Presynaptic a Depression b Facilitation Postsynaptic c Desensitization d Saturation Figure 1 | Presynaptic and postsynaptic mechanisms of short-term plasticity. Schematized voltage-clamp traces illustrate the influence of two presynaptic mechanisms (a, b) and two postsynaptic mechanisms (c, d) of plasticity on a pair of excitatory postsynaptic currents (EPSCs). Cartoons of presynaptic boutons illustrate possible explanations for presynaptic depression (a) and facilitation (b) and cartoons of postsynaptic spines illustrate desensitization (c) and saturation (d). a | Top, presynaptic depression results in a smaller second EPSC. Bottom, fewer vesicles are available for release on the second (right) stimulus than on the first (left). b | Top, facilitation results in a larger second EPSC. Bottom, a residual elevation in intracellular calcium (green shading), combined with the influx of calcium in response to the second stimulus, results in enhanced release. c | Top, similar to depression, desensitization results in a smaller second EPSC. Bottom, under prolonged exposure to transmitter, some receptors can enter a non-responsive state (red crosses, right) and be unable to respond to transmitter released during a second stimulus. d | Top, channels with slow kinetics (such as NMDA (N-methyl-D-aspartate) channels) that experience saturation can produce a large amount of current following a second stimulus, despite the smaller incremental amplitude of the second EPSC, owing to summation with the previous EPSC. Bottom, for receptors with high affinity for the transmitter, a population of receptors can remain bound with transmitter (red circles) and therefore be unavailable to respond to the transmitter released in response to a second stimulus. the mechanisms that lead to short-term synaptic plasticity, and at most synapses multiple mechanisms are present that interact and lead to complex responses during realistic patterns of synaptic activation. Much attention is focused on understanding the mechanisms that underlie such short-term synaptic plasticity and its functional consequences. Here, rather than providing a comprehensive overview, we explore the functional consequences of short-term synaptic plasticity by comparing two synapses: the synapse between retinal ganglion cells and thalamocortical relay neurons (the retinogeniculate synapse) and the synapse between climbing fibres and cerebellar Purkinje cells. Despite superficial similarities, use-dependent plasticity at these synapses leads to profound functional differences during realistic patterns of activity. NATURE REVIEWS | NEUROSCIENCE Climbing fibre synapses are made by neurons in the inferior olive onto Purkinje cells in the cerebellum32. In the adult, there is only one climbing fibre input for each Purkinje cell, and it forms several hundred synaptic contacts onto proximal Purkinje cell dendrites33,34 (FIG. 2a). Activation of climbing fibres releases glutamate, which in turn activates AMPA receptors on the Purkinje cell. The size of this synaptic response can be quantified under voltage-clamp conditions, where the postsynaptic cell is maintained at a given potential, enabling synaptic currents to be measured without interference from postsynaptic activity (FIG. 2b). The EPSC that is elicited by a single climbing fibre is large and has a maximal conductance of 300–500 nS. If the response is measured in current-clamp mode and the cell is allowed to respond naturally, climbing fibre activation leads to a series of regenerative responses, collectively known as a complex spike35 (FIG. 2c). So, the climbing fibre provides a powerful and reliable signal to Purkinje cells. The retinogeniculate synapse is similar in many ways. Between one and three retinal ganglion cells (RGCs) provide a powerful synaptic drive to each thalamocortical relay neuron in the lateral geniculate nucleus (LGN) of the thalamus36,37. As with climbing fibres, each retinogeniculate input consists of many synaptic contacts onto the proximal dendrites of a thalamocortical neuron38 (FIG. 2d). Voltage-clamp recordings reveal that the retinogeniculate synaptic response is also a large synaptic current (FIG. 2e) with a maximal conductance of 10–40 nS. In current-clamp mode, a single stimulus reliably elicits a spike in the thalamocortical neuron (FIG. 2f). This finding indicates that the retinogeniculate synapse can reliably activate relay neurons in the LGN and thereby provides a secure means of relaying visually evoked responses from the retina to the thalamus and, ultimately, to the visual cortex. These anatomical features and the fact that both synapses can reliably evoke spikes in their postsynaptic targets indicate that they are well suited to provide powerful and reliable synaptic drive to their postsynaptic targets. However, this view is based on responses to stimulation at low frequencies and does not reflect the contributions of synaptic plasticity that could occur under higher-frequency, physiological activity patterns. As we discuss below, differences in presynaptic firing patterns and short-term synaptic plasticity at these synapses result in vastly different activation responses under physiological conditions. The differences at these two synapses indicate that short-term synaptic plasticity leads to distinctive characteristics that reflect the specific roles of each type of synapse. The climbing fibre synapse Reliability is important for the climbing fibre synapse because climbing fibre activity is suggested to provide an error signal that is important in cerebellar motor learning. This process is thought to occur, at least in part, in the cerebellar cortex through long-term VOLUME 5 | AUGUST 2004 | 6 3 1 ©2004 Nature Publishing Group REVIEWS d a 20 µm 20 µm b e 1 nA 1 nA 10 ms 10 ms c f 0 2 ms Vm (mV) Vm (mV) 0 10 ms –55 –60 Figure 2 | A comparison of the climbing fibre and retinogeniculate synapses. a | Confocal image of a Purkinje cell labelled with the fluorescent dye Alexa 568 hydrazide, and a calcium green dextran-labelled climbing fibre. This indicates the relationship of the climbing fibre to the Purkinje cell dendrite. Reproduced, with permission, from REF. 129 © (2000) Elsevier Science. b,c | A voltage-clamp recording illustrates that a single climbing fibre stimulus elicits a large inward current (b), while a current-clamp recording shows that the same stimulus elicits a complex spike in the Purkinje cell (c). d | A reconstruction of a thalamocortical neuron, with the locations of retinal ganglion cell (RGC) synaptic contacts indicated by red dots. Reproduced, with permission, from REF. 38 © (1987) John Wiley & Sons, Ltd. e,f | A trace recorded in voltage-clamp mode shows that a single stimulus to an RGC axon in the optic tract elicits a large inward current in a postsynaptic thalamocortical neuron (e). In current-clamp mode, the same single RGC activation elicits an excitatory postsynaptic current that is sufficiently large to elicit an action potential (f). PAIRED-PULSE DEPRESSION A decrease in the amplitude of the second of two closely timed excitatory postsynaptic currents. It can result presynaptically from a decrease in the amount of neurotransmitter released or postsynaptically as a result of desensitization. 632 depression (LTD) of granule cell synapses onto Purkinje cells39–41. In addition to the excitatory input provided by climbing fibres, each Purkinje cell receives about 100,000 inputs from granule cells34,42,43. Climbing fibre activation initiates a complex spike that depolarizes the dendritic arbour of Purkinje cells and leads to calcium entry 44,45. This widespread electrical and calcium signal contributes to LTD of granule cell synapses that are activated at about the same time as the climbing fibre46,47. To elicit LTD repeatedly, the climbing fibre must powerfully and reliably activate Purkinje cells during patterns of activity that are encountered in vivo. | AUGUST 2004 | VOLUME 5 Typically, the climbing fibre fires at about 1 Hz, but it can also fire bursts of 3 action potentials at between 5 and 15 Hz in response to sensory stimuli48–50. The response of the Purkinje cell to this type of activity pattern can be evaluated in cerebellar slice preparations by recording from a Purkinje cell in current-clamp mode. When a 15-Hz train of 3 pulses is delivered, the Purkinje cell fires a complex spike in response to each stimulus30 (FIG. 3a). Although there are slight differences between these complex spikes, overall they are remarkably consistent. The consistency of the Purkinje cell response indicates that the climbing fibre provides a powerful input to the Purkinje cell and maintains its efficacy during physiological activity patterns. To understand how the climbing fibre drives the Purkinje cell so reliably, it is useful to measure the synaptic currents that give rise to the postsynaptic response under voltage-clamp conditions. These currents are mediated solely by AMPA receptors, as NMDA receptors are eliminated from the climbing fibre synapse early in postnatal development51,52. When a similar pattern of excitation is applied to the climbing fibre while the Purkinje cell is held in voltage-clamp, the resulting EPSCs undergo little depression (FIG. 3b). This indicates that, on this timescale, short-term plasticity does not make an important contribution to transmission. Three main factors explain this lack of plasticity. First, AMPA receptor desensitization, which can contribute to depression at other synapses, is not prominent at the climbing fibre synapse53–55. Second, although climbing fibres show pronounced depression on a short timescale, recovery from depression is accelerated by presynaptic accumulation of calcium30,54. Third, multivesicular release and receptor saturation at this synapse make the Purkinje cell relatively insensitive to changes in the amount of transmitter released29–31. By examining these three aspects of transmission, we can better understand how the climbing fibre synapse is specialized to drive the Purkinje cell so reliably. Desensitization. Although climbing fibre synapses seem to have a high probability of release, which leads to activation of a large fraction of postsynaptic AMPA receptors, desensitization of these receptors does not contribute to PAIRED-PULSE DEPRESSION at this synapse53–55. This is interesting in light of the fact that receptors in patches pulled from the soma or dendrites do undergo desensitization in response to puffs of glutamate29,56. The fact that desensitization of AMPA receptors contributes little to synaptic depression might result in part from the structure of climbing fibre synapses. Although climbing fibres make hundreds of synaptic contacts onto Purkinje cells, each contact and its associated postsynaptic density on the Purkinje cell is isolated from neighbouring synapses by BERGMANN GLIAL ensheathment57. Bergmann glia express a high density of glutamate transporters58,59, so they can probably terminate glutamate signals rapidly and prevent glutamate from pooling and spilling over to neighbouring sites. In addition, recovery from desensitization is relatively rapid29,56, which might allow recovery from desensitization between stimuli. www.nature.com/reviews/neuro ©2004 Nature Publishing Group REVIEWS a Vm (mV) 0 50 ms –20 –40 –60 b 1 nA 50 ms c 1.0 EPSC2/EPSC1 Calcium-dependent recovery from depression. The second factor that contributes to the reliability of climbing fibre synapses is that elevated presynaptic calcium accelerates recovery from depression30,54. This is illustrated by examining the time dependence of the depression that occurs for pairs of EPSCs that are separated by different time intervals. Recovery of paired-pulse depression at the climbing fibre synapse occurs in two phases — a fast component with a time constant of 100 ms that accounts for 45% of recovery and a slow component with a time constant of 2.5 s that accounts for the remaining 55% (REF. 30)(FIG. 3c, green circles). These two phases of recovery indicate that some sites become release-competent much faster than others. Decreasing the concentration of extracellular calcium decreases the amplitude of the rapid component of recovery, as does chelating presynaptic calcium with EGTA (FIG. 3c, blue circles). Therefore, accelerated recovery is driven by presynaptic calcium that enters during the action potential. This accelerated recovery helps minimize depression during ongoing activity and might have a similar role at other synapses60–62. 0.5 Control 0.6 EGTA 0.2 0.2 0.0 BERGMANN GLIA Astrocytes that are located in the cerebellum with their cell bodies close to a Purkinje cell. They extend radial fibres along the dendritic tree of the Purkinje cell and ensheath synapses made by the climbing fibre and parallel fibres. Receptor saturation. The third factor that allows the climbing fibre to evoke a consistent response in the Purkinje cell is that the release of several vesicles at each release site in response to an action potential provides a glutamate signal that is sufficient to saturate the postsynaptic receptors29. This was shown using the lowaffinity AMPA receptor antagonist γ-D-glutamylglycine (γDGG), which has exceptionally rapid kinetics. The key observation was that γDGG reduced the EPSC to a greater extent when the synapse was depressed after high-frequency stimulation than it did otherwise29 (FIG. 3d). To interpret these experiments it is necessary to consider that γDGG and glutamate compete for binding sites on the AMPA receptor.Although synaptically evoked glutamate is rapidly removed from the synaptic cleft after release (within milliseconds), the fast kinetics of γDGG allow it to compete with glutamate during this time. The efficacy of γDGG depends on the concentration of glutamate in the cleft. The smaller the glutamate signal, the more effectively γDGG can compete and the larger the effect of γDGG on the EPSC. Therefore the more effective block of AMPA receptors by γDGG when depression is prominent is the result of a lower concentration of glutamate in the synaptic cleft. One possible explanation is that spillover from neighbouring sites is prominent when the probability of release is high and that this increases the amount of glutamate at a given release site. However, each release site seems to be well isolated from its neighbours by glial ensheathment57, so this explanation is unlikely. Instead, the differential effects of γDGG indicate that more vesicles are released at an individual site on the first stimulus than on the second, when the EPSC is depressed. The difference in the amount of depression with and without γDGG also indicates that under control conditions, when γDGG is not present, postsynaptic AMPA receptors are saturated. Saturation of the postsynaptic receptors renders the Purkinje cell less sensitive to changes in the amount of NATURE REVIEWS | NEUROSCIENCE 0.0 0 5 10 Time (s) d 1 nA 1 nA 30 ms 30 ms Control DGG Figure 3 | Recovery from depression and saturation at the climbing fibre to Purkinje cell synapse. a | Current-clamp recording from a Purkinje cell. The climbing fibre elicits three similar complex spikes in the Purkinje cell when stimulated with three pulses at 15 Hz. b | Voltage-clamp recording from a Purkinje cell reveals that the postsynaptic currents elicited by stimulating the climbing fibre with this pattern are similar in amplitude. c | The time-course of recovery from depression under control conditions (green circles) and in the presence of EGTA to chelate intracellular calcium (blue circles). Recovery occurs with an initial rapid phase and a second slower phase. The inset shows these same curves on an expanded timescale. d | Voltage-clamp recordings from a Purkinje cell showing a pair of excitatory postsynaptic currents generated by stimulating the climbing fibre twice at 50-ms intervals under control conditions (left) and in the presence of γ-D-glutamylglycine to relieve AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor saturation (right). Modified, with permission, from REF. 30 © (2002) Elsevier Science. glutamate that is released by the climbing fibre, which reduces the effects of depression at this synapse. This is because under physiological conditions the receptors are overwhelmed by the amount of glutamate released, resulting in an EPSC that is an underestimate of the amount of neurotransmitter released. As a result, subsequent depressed EPSCs that result from smaller glutamate transients are closer to the size of the first EPSC than if there were a linear relationship between VOLUME 5 | AUGUST 2004 | 6 3 3 ©2004 Nature Publishing Group REVIEWS the EPSC amplitude and the amount of glutamate released. Furthermore, the rate of recovery from depression is increased because recovery to the maximum EPSC amplitude occurs before complete recovery of the glutamate transient. Overall, receptor saturation minimizes the effects of decreased transmitter release on the postsynaptic cell. Complex synaptic mechanisms. Many forms of synaptic plasticity work together at the climbing fibre synapse to ensure a roughly constant synaptic response, even though it seems that some depression is unavoidable at synapses where the probability of release is high. High-frequency activity that tends to depress transmission is counteracted by accelerated recovery from depression that is driven by a buildup of presynaptic calcium concentrations. Multivesicular release and receptor saturation also minimize the effects. These mechanisms combine to ensure that the postsynaptic conductance is relatively constant even in the face of reduced neurotransmitter release. So, the initial apparent simplicity of the climbing fibre synapse is misleading. The ability to maintain a roughly constant synaptic response under physiological conditions reflects the interaction of many synaptic specializations. The retinogeniculate synapse Despite similarities in the ability of a single stimulus to elicit a postsynaptic spike at the climbing fibre and the retinogeniculate synapses, there are important differences between these synapses that are consistent with specializations that are suited to different functional roles. Specifically, the function of the retinogeniculate synapse is to transfer visual information contained in the firing patterns of RGCs to thalamocortical neurons in the LGN. Although the large amplitude of the RGC-elicited excitatory postsynaptic potentials (EPSPs) and their ability to reliably evoke firing in thalamocortical neurons in response to low-frequency activation indicate that the retinogeniculate synapse simply relays RGC activity to thalamocortical neurons, this is not the case. The resting potential of thalamocortical neurons can greatly influence the transfer of visual signals across the retinogeniculate synapse. At hyperpolarized membrane potentials, thalamocortical neurons are in burst mode, and excitatory inputs activate low-threshold calcium channels that can elicit bursts of action potentials63–66. At more depolarized potentials, the low-threshold calcium channels are inactivated, and thalamocortical neurons are in a tonic response mode64,67,68. Although visual stimuli can elicit responses in both tonic and burst mode, neurons in the awake animal are more commonly in tonic mode69–71. Here we focus on how synaptic plasticity influences retinogeniculate transmission when thalamocortical neurons are in tonic mode. Paired extracellular recordings of RGCs and thalamocortical neurons during visual stimulation show that even at apparently strong synaptic connections, an individual RGC spike does not always elicit a postsynaptic action potential37,72,73. This is illustrated in simultaneous extracellular recordings of a RGC and a thalamocortical neuron (FIG. 4a). In the small interval shown from such a 634 | AUGUST 2004 | VOLUME 5 recording in FIG. 4a, there are fourteen RGC spikes and nine thalamocortical neuron spikes. Seven of the RGC spikes (yellow triangles) trigger no response, five of the RGC spikes (blue triangles) trigger single short-latency, precisely timed spikes, and two of the RGC spikes (black triangles) trigger a burst of two spikes each (FIG. 4a). The appearance of multiple spikes per presynaptic action potential indicates that this synapse can amplify incoming information from the retina, which may be important for activating cortical neurons73,74. The prominence of bursts of spikes in thalamocortical neurons is often taken to be a hallmark of a cell in burst mode. However, as we will explore below, the properties of the retinogeniculate synapse can also lead to bursts of action potentials when thalamocortical neurons are in tonic mode. Besides variability in the number of spikes elicited, there is also variability in the timing of elicited spikes relative to the presynaptic spikes. In addition to shortlatency, precisely timed spikes, thalamocortical neurons can also have delayed responses, indicating that the synapse can alter the timing of visual information that is relayed to the cortex37,73,75. Furthermore, in vivo, the timing between RGC spikes has been shown to influence their efficacy in eliciting thalamocortical neuron spikes73,75–77. Unlike the physiological activity patterns of climbing fibres, RGCs can fire over a large range of frequencies with a great deal of variety in their patterns of activity78–82. A dependence of efficacy on RGC spike timing could relay additional information about the patterns of RGC activity. So, in vivo observations indicate that this synapse does not simply relay visual signals but instead processes them and helps to control the visual information that reaches the cortex. AMPA and NMDA currents. Unlike the climbing fibre-to-Purkinje cell synapse, transmission at the retinogeniculate synapse is mediated by both AMPA and NMDA receptors83–87. To understand how properties of the retinogeniculate synapse contribute to the complex transformation of RGC spikes into thalamocortical neuron activity, it is necessary to consider both the AMPA and NMDA components. These two receptor types mediate currents with different properties88–90. Currents elicited by AMPA receptors at the retinogeniculate synapse have a linear current–voltage relationship and rapid kinetics91,92. However, currents through NMDA receptors have a nonlinear current–voltage relationship because, at hyperpolarized membrane potentials, the channel is blocked by magnesium92–95. NMDA currents also have slower kinetics than AMPA currents96,97. These properties make NMDA currents suited to their established role in several forms of long-term synaptic plasticity98–100. NMDA receptors are also important in eliciting postsynaptic firing92,101–104. In vivo experiments using receptor antagonists in the LGN showed that both AMPA and NMDA currents contribute to visually evoked responses in thalamocortical neurons83,84,86,105 (FIG. 4b). Although NMDA channels often require the postsynaptic cell to be depolarized by AMPA receptors before they can be activated sufficiently to elicit spikes, www.nature.com/reviews/neuro ©2004 Nature Publishing Group REVIEWS c Stimulus a NMDA 0.1 s AMPA Control Control Spikes s–1 300 0 300 500 pA 0 1.0 0 300 Spikes s–1 Spikes s–1 1.0 Time (s) No plasticity 30 30 0 0 0 0 0 –55 –55 1.0 Recovery 300 Depression only 30 1.0 0 1.0 Recovery Desens + depression d g (nS) Spikes s–1 Spikes s–1 d-APV 300 0 100 ms 1.0 CNQX Vm (mV) Spikes s–1 b 300 0 Time (s) 0 –55 100 ms Figure 4 | AMPA and NMDA receptor contributions to retinogeniculate transmission. a | Thalamocortical neuron (bottom) and retinal ganglion cell (RGC; top) spike trains in vivo illustrate that an individual RGC action potential can elicit zero (white triangles), one (blue triangles) or multiple spikes (black triangles) in a thalamocortical neuron. Data courtesy of W. M. Usrey, J. B. Reppas and R. C. Reid, Harvard Medical School. b | In vivo the lateral geniculate nucleus (LGN) neuron responses to visual stimuli are represented as peri-stimulus time histograms under control conditions (top), in the presence of the AMPA and NMDA receptor antagonists CNQX (6-cyano-7- nitroquinoxaline-2,3-dione) (middle, left) and d-APV (D(–)-2-amino-5-phosphonovaleric acid) (middle, right), and during recovery from drug application (bottom). Lines below graphs indicate time of light presentation. CNQX and d-APV were applied by iontophoresis into the LGN. Modified, with permission, from REF. 86 © (1991) American Physiological Society. c | Voltage-clamp traces illustrate isolated NMDA (N-methyl-D-aspartate, middle) and AMPA (α-amino-3-hydroxy-5-methyl4-isoxazole propionic acid, bottom) currents in response to RGC axon stimulation with the stimulus train shown above recordings. Isolated NMDA and AMPA currents were recorded in the presence of 5 µM NBQX (6-nitro-7-sulphamoylbenzo(f)quinoxaline-2,3dione, an AMPA receptor antagonist) and 5 µM CPP (3-+-(2-carboxypiperazin–4-yl)propyl-1 phosphonic acid, an NMDA receptor antagonist), respectively. Each trace is the average of five trials. Modified, with permission, from REF. 9 © (2002) Elsevier Science. d | Thalamocortical neuron responses (bottom) to dynamic-clamp AMPA conductance waveforms (top) recorded in a slice preparation are shown. Conductance waveforms with the influence of desensitization and depression present (left), with the influence of only depression present (middle), and with no plasticity present were injected (right). Modified, with permission, from REF. 95 © (2003) American Physiological Society. NMDA currents alone elicit some action potentials in response to visual stimuli (FIG. 4b). This is probably due to the current–voltage relationship of NMDA currents at the retinogeniculate synapse. When thalamocortical neurons are in tonic mode, despite the magnesium block of NMDA channels, NMDA current is elicited by activation of the retinogeniculate synapse in the absence of any depolarization93,95. Blockade of AMPA receptors reduces the initial component of the responses more than blockade of NMDA receptors (FIG. 4b). However, NMDA receptor blockade has more influence on the later portion of the response, where AMPA receptor blockade has little effect. These data show that AMPA receptors make a small contribution late in a train of RGC activity 86. This is surprising given the large amplitude of individual AMPA currents in response to a single stimulus (FIG. 2e). An examination of EPSCs that are evoked by physiological patterns of activity helps to explain the observed contributions of NMDA receptors and AMPA receptors to visually evoked responses in thalamocortical neurons. The retinogeniculate synapse has been studied in a slice preparation that includes the optic tract, making it possible to activate single RGC inputs. The properties of NATURE REVIEWS | NEUROSCIENCE the retinogeniculate synapse can be studied without interference of active conductances by studying the response under voltage-clamp, and without the complications of inhibitory synapses by including GABA (γ-aminobutyric acid) receptor antagonists. In response to a physiological stimulation pattern, AMPA currents in thalamocortical neurons are highly depressed during higher frequency stimuli, but recover substantially during long interstimulus intervals9 (FIG. 4c). The small AMPA receptor contribution during sustained highfrequency activity reflects activity-dependent plasticity and helps to explain why AMPA receptors apparently become less effective during sustained visual stimulation (FIG. 4b). The response of the NMDA component is quite different. Although NMDA receptor EPSCs are also depressed during trains, the much longer duration of NMDA currents causes summation and, as a result, a large NMDA current remains despite depression9 (FIG. 4c). This indicates that the properties of the NMDA currents can overcome the influence of short-term plasticity and enable NMDA receptors to continue to mediate visually evoked responses in thalamocortical neurons during sustained visual stimulation (FIG. 4b). VOLUME 5 | AUGUST 2004 | 6 3 5 ©2004 Nature Publishing Group REVIEWS DYNAMIC-CLAMP A technique to introduce artificial synaptic or voltagegated conductance into a neuron. The time course, voltage dependence and reversal potential are measured under voltage-clamp conditions and are used to determine the appropriate current to be injected to mimic the synaptic conductance by the dynamicclamp technique, in currentclamp recording mode. 636 AMPA receptor desensitization contributes prominently to the use-dependent plasticity of the AMPA component9. The probability of release at the retinogeniculate synapse has not been quantified to the degree that it has at the climbing fibre synapse. Based on the amount of presynaptic depression, it is likely to be approximately 0.3 (REF. 9), which is much lower than at the climbing fibre synapse. However, anatomical specializations probably account for the contributions of AMPA receptor desensitization to use-dependent plasticity at this synapse. Unlike at the climbing fibre synapse, at the retinogeniculate synapse there are many release sites in close proximity without glial separation106. This arrangement also occurs at other synapses at which desensitization contributes to depression, including auditory nerve fibre synapses onto nucleus magnocellularis neurons, and cerebellar mossy fibre synapses onto granule cells27,28. Many release sites in close proximity allow glutamate pooling, and enable glutamate from one release site to bind to and cause desensitization of AMPA receptors at a neighbouring release site. As a result, glutamate release at this neighbouring site will be less effective if it occurs before these receptors have recovered from desensitization (FIG. 1c). Because desensitization recovers within around 100 ms (REFS 9,27,28), this form of plasticity attenuates AMPA currents at high firing frequencies. The anatomy of the retinogeniculate synapse has different consequences for NMDA currents during high-frequency activity. Because NMDA receptors have a high affinity for glutamate, spillover of glutamate that can occur with many closely spaced release sites can effectively activate a particularly large fraction of NMDA receptors and lead to their partial saturation. As a result of the slow kinetics of NMDA receptors, glutamate will still be bound to many receptors if a second stimulus occurs a short time later (FIG. 1d). This partial saturation of NMDA receptors results in fewer receptors being available to mediate additional current, as indicated in FIG. 4c by the smaller incremental currents during a train of RGC action potentials9. However, the slow kinetics of NMDA receptors lead to a large total NMDA conductance during high-frequency activity. This differs from AMPA currents, which are minimal during high-frequency activity owing to desensitization9 (FIG. 4c). These differences in postsynaptic plasticity of the two components probably contribute to the differences in their roles during the early and late portions of visual stimulation86 (FIG. 4b). Functional consequences of plasticity. To understand how plasticity at this synapse contributes to shaping thalamocortical neuron responses, it is useful to allow the neurons to respond naturally in current-clamp mode and to manipulate the components of plasticity individually. However, pharmacological isolation of different forms of short-term plasticity in current-clamp is impractical. Presynaptic depression cannot be manipulated without altering other neuronal properties. Similarly, pharmacological manipulation of AMPA | AUGUST 2004 | VOLUME 5 receptor desensitization has prominent secondary effects, such as changing the time course of synaptic currents, which can alter thalamocortical neuron responses independently of plasticity owing to desensitization9,10,27. Therefore, a different approach must be used. The DYNAMIC-CLAMP technique provides a powerful means of manipulating individual aspects of shortterm plasticity and examining their influence on neuronal responses107. Dynamic-clamp allows the researcher to mimic synaptic inputs and record the neuronal responses. The amplitude and kinetics of the synaptic conductances can be controlled and manipulated, and properties such as the nonlinear current–voltage relationship of NMDA receptors can be incorporated. Furthermore, mechanisms of synaptic plasticity can be included and manipulated individually95,107. Voltage-clamp analysis of the short-term plasticity of AMPA and NMDA currents at the retinogeniculate synapse provided the information that was necessary for successful application of the dynamicclamp approach9,95. Dynamic-clamp studies of the AMPA component of the retinogeniculate synapse revealed that depression and desensitization severely limit the efficacy of AMPA currents during a train of RGC input. The large amplitude of an initial AMPA excitatory postsynaptic conductance (EPSG) is always effective at eliciting an action potential in a thalamocortical neuron. However, subsequent AMPA EPSGs are ineffective when both depression and desensitization shape EPSG amplitudes (FIG. 4d, left). In the absence of desensitization, more AMPA EPSGs are effective at eliciting spikes (FIG. 4d, middle). In the absence of desensitization and depression, AMPA EPSGs are effective throughout a stimulus train (FIG. 4d, right). So, activity-dependent plasticity severely limits the efficacy of the AMPA component at the retinogeniculate synapse during sustained RGC activity95. Consequently, AMPA currents can make a much greater contribution to the postsynaptic response after quiescent periods than during sustained high-frequency activity. These data explain in vivo findings that AMPA receptors are not very effective at conveying the late component of a visually evoked response (FIG. 4b). By contrast, the summation of NMDA currents allows them to make greater contributions during periods when the AMPA component contributes little to the response86. Distinctions between AMPA and NMDA components also result in different contributions of AMPA receptors and NMDA receptors to the responses of thalamocortical neurons to individual presynaptic action potentials. Pharmacological experiments in vitro reveal that the AMPA component elicits one shortlatency, precisely timed action potential for each RGC spike. However, the NMDA component elicits action potentials with longer, more variable latencies and can elicit multiple action potentials per presynaptic spike95. The properties of the AMPA and NMDA components, therefore, explain why thalamocortical neuron responses are not simple relays of RGC input. www.nature.com/reviews/neuro ©2004 Nature Publishing Group REVIEWS a Cell 1 Cell 2 Cell 3 Cell 4 Cell 5 Cell 6 Cell 7 0 500 1,000 1,500 2,000 2,500 Time (ms) b Vm (mV) 0 –55 0 0.6 0 Time (s) c A20, N10 0 0.6 0.6 Time (s) Time (s) A40, N10 A30, N40 Vm (mV) 0 –55 Cell 1 Cell 2 Cell 3 Cell 4 Cell 5 Cell 6 0 0.6 0 Time (s) 0.6 Time (s) 0 0.6 Time (s) Figure 5 | AMPA and NMDA component amplitudes contribute to variability in response spike number and timing between different thalamocortical neurons. a | The responses of seven thalamocortical neurons to multiple presentations of the same visual stimulus in vivo are shown as raster plots. Visual stimulus onset is at time zero and is ongoing for the duration illustrated. Modified, with permission, from REF. 108 © (2002) Society for Neuroscience. b | Responses of three thalamocortical neurons in a slice preparation to retinal ganglion cell axon stimulation are shown. Stimulus pattern is indicated above the traces. Raster plots of 2–3 trials per cell are plotted below. c | Responses of a single thalamocortical neuron to injection of AMPA and NMDA conductances with dynamic-clamp are shown. AMPA (α-amino-3-hydroxy-5-methyl4-isoxazole propionic acid, A) and NMDA (N-methyl-D-aspartate, N) conductance amplitudes are indicated above traces. Raster plots of four trials each for six neurons for each conductance combination are plotted below. Parts b and c modified, with permission, from REF. 95 © (2003) American Physiological Society. NATURE REVIEWS | NEUROSCIENCE Response reproducibility and variability. The responses of individual thalamocortical neurons in vivo to repeated presentations of a visual stimulus are highly reproducible108 (FIG. 5a). In contrast, spike number and timing vary between thalamocortical neurons108 (FIG. 5a). These characteristics are also found in the slice preparation, even when all other influences, such as cortical feedback and inhibitory circuitry, are eliminated. A train of stimuli delivered to an RGC input in a slice preparation elicits reproducible responses during repeated trials in a single thalamocortical neuron and different responses in different thalamocortical neurons (FIG. 5b). These responses vary from failures during the response (FIG. 5b, left), to a faithful representation of the pattern (FIG. 5b, middle) or a pattern that includes additional action potentials95 (FIG. 5b, right). The similarities between in vivo findings and in vitro findings when thalamocortical neurons are isolated from other influences indicates that differences in responses between thalamocortical neurons are due to properties of the retinogeniculate synapse. Differences in the magnitude of AMPA and NMDA currents between synapses contribute to differences in thalamocortical neuron responses95. The range of responses that are elicited by synaptic inputs is replicated by injecting different combinations of artificial AMPA and NMDA conductance amplitudes using dynamicclamp. Responses vary from containing failures (FIG. 5c, left), to being faithful representations of the presynaptic pattern (FIG. 5c, middle), to containing additional spikes (FIG. 5c, right), in a manner that is similar to visually evoked thalamocortical neuron responses observed in vivo. The response of an individual thalamocortical neuron can be readily switched between these responses by altering the combination of AMPA and NMDA conductances that is injected (FIG. 5c, top). For example, a larger NMDA component can amplify RGC input by eliciting multiple postsynaptic spikes per presynaptic spike95 (FIG. 5c, right). This indicates that RGC input can be amplified in thalamocortical neurons even when they are not in burst mode. However, in tonic mode the bursts are mediated by NMDA currents whereas in burst mode they are mediated by low-threshold calcium channels66,109. Such differences in responses owing to the combination of AMPA and NMDA conductances are probably important for how visual information is passed onto cortical neurons, as these neurons respond more strongly to the second of two closely spaced stimuli110–112. These experiments show that a single thalamocortical neuron can generate various responses simply by altering the AMPA and NMDA conductances. So, although other factors such as intrinsic properties of thalamocortical neurons and local circuitry might contribute to differences in responses between thalamocortical neurons, these data support the idea that differences in responses between thalamocortical neurons are a consequence of the properties of the retinogeniculate synapse. The properties of the retinogeniculate synapse result in a dynamic transfer of visual information. The plasticity of AMPA currents severely limits their efficacy during sustained high-frequency activity, and the long duration VOLUME 5 | AUGUST 2004 | 6 3 7 ©2004 Nature Publishing Group REVIEWS of the NMDA currents enhances their contributions during sustained activity. This can change the nature of thalamocortical neuron responses from precisely timed, short-latency action potentials after a quiescent period to longer-latency bursts of multiple action potentials per presynaptic spike during sustained activity. Furthermore, the relative balance of AMPA and NDMA currents and their maximal conductances can result in different responses to the same RGC activity pattern. The transfer ratio at this synapse can range from low to high depending on the contributions of these two synaptic currents. Consequently, how RGC input is transformed into thalamocortical neuron firing will have important implications for the visual information that is transferred to cortical neurons. General implications Although the climbing fibre and retinogeniculate synapses are both powerful synapses, they have many specializations that result in functional differences. The climbing fibre synapse uses multiple mechanisms to produce a reliable response to repetitive activation that is stereotyped in different Purkinje cells. The plasticity of the retinogeniculate synapse, however, transforms the presynaptic activity pattern into a postsynaptic response that is dynamically regulated throughout a train and that can endow different retinogeniculate synapses with a range of properties. These two synapses illustrate the importance of synaptic plasticity and synaptic specializations in determining the effect of a cell on the firing of its targets. Short-term plasticity also has important functional consequences at other synapses12–14,113–115. Synapses with a high probability of release, such as the climbing fibre and retinogeniculate synapses, tend to undergo shortterm depression, which can have important behavioural consequences. For example, depression at thalamocortical synapses in barrel cortex underlies the behavioural adaptation to whisker deflections115. In the visual cortex, synaptic depression at synapses between layer 4 and layer 2/3 equalizes the postsynaptic response to changes in the firing frequency of rapidly and slowly firing inputs12. Depression is also important in the crustacean pyloric network. Here, the extent of depression at a synapse between a circuit neuron and the pacemaker neurons controls the frequency of oscillation of the pacemaker neurons and, therefore, of the rhythm that is generated by this circuit113. 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It can be difficult to determine the functional consequences of short-term plasticity at many other synapses. In contrast to the synapses discussed in this review, synapses are often small and influence firing only by acting with other synaptic inputs and by interacting with intrinsic conductances in the postsynaptic cell117–119. In hippocampal CA1 pyramidal neurons, for example, EPSPs are amplified by their interaction with intrinsic currents that can lead to the generation of plateau potentials. The influence of EPSPs on postsynaptic firing therefore depends on the properties of the intrinsic currents that are activated115, and the consequences of short-term plasticity will be complicated by how it affects the activation of these currents. In considering how such small synaptic inputs activate their targets, it is often necessary to consider the spatial location of inputs on the dendritic arbour as well as voltage-gated channels120–122. 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