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• W1963878275 abstract "Mammalian axons are thought to act as digital signaling devices, conveying information only by the timing and rate of all-or-none action potentials. Two recent studies now show that synaptic potentials can also spread far down the axon and influence action potential-triggered transmitter release in a graded, ‘analog’ manner. Axons thus encode information both about subthreshold and suprathreshold synaptic activity. Mammalian axons are thought to act as digital signaling devices, conveying information only by the timing and rate of all-or-none action potentials. Two recent studies now show that synaptic potentials can also spread far down the axon and influence action potential-triggered transmitter release in a graded, ‘analog’ manner. Axons thus encode information both about subthreshold and suprathreshold synaptic activity. Axons connect neurons. They are signalling devices, transmitting action potentials which trigger neurotransmitter release from synaptic boutons along the axon. In the classical view, synaptic input to the soma and dendrites of a neuron is funnelled into the axon, and at the initiation site — in the axon initial segment or first node of Ranvier [1Coombs J.S. Curtis D.R. Eccles J.C. The interpretation of spike potentials of motoneurones.J. Physiol. 1957; 139: 198-231Crossref PubMed Scopus (211) Google Scholar, 2Clark B.A. Monsivais P. Branco T. London M. Hausser M. The site of action potential initiation in cerebellar Purkinje neurons.Nat. Neurosci. 2005; 8: 137-139Crossref PubMed Scopus (109) Google Scholar, 3Palmer L.M. Stuart G.J. Site of action potential initiation in layer 5 pyramidal neurons.J. Neurosci. 2006; 26: 1854-1863Crossref PubMed Scopus (228) Google Scholar] — a decision is made to fire an action potential once a threshold level of depolarization is exceeded. As the action potential is an all-or-none signal, it can be viewed as a ‘digital’ signal, with its initiation thus representing an analog-to-digital conversion. The action potential is then transmitted down the axon to the synaptic boutons, where it serves as the necessary trigger for synaptic release. Action potential propagation is thought to be quite reliable, making axons relatively uninteresting in signal processing terms, acting as simple point-to-point relays. Furthermore, in this view, the information transmitted by axons is solely encoded by the number and timing of action potentials in the axon. Two recent studies [4Alle H. Geiger J.R. Combined analog and action potential coding in hippocampal mossy fibers.Science. 2006; 311: 1290-1293Crossref PubMed Scopus (277) Google Scholar, 5Shu Y. Hasenstaub A. Duque A. Yu Y. McCormick D.A. Modulation of intracortical synaptic potentials by presynaptic somatic membrane potential.Nature. 2006; 441: 761-765Crossref PubMed Scopus (310) Google Scholar] have challenged this view. Using sophisticated techniques to make whole-cell patch-clamp recordings directly from the axons of neurons in brain slices, Alle and Geiger [4Alle H. Geiger J.R. Combined analog and action potential coding in hippocampal mossy fibers.Science. 2006; 311: 1290-1293Crossref PubMed Scopus (277) Google Scholar] and Shu et al.[5Shu Y. Hasenstaub A. Duque A. Yu Y. McCormick D.A. Modulation of intracortical synaptic potentials by presynaptic somatic membrane potential.Nature. 2006; 441: 761-765Crossref PubMed Scopus (310) Google Scholar] have shown, in two different neuronal types, that, in addition to action potentials, axons can transmit subthreshold synaptic potentials surprisingly efficiently (Figure 1), and that this spread of subthreshold potentials can have a significant impact on synaptic transmission triggered by action potentials. Alle and Geiger [4Alle H. Geiger J.R. Combined analog and action potential coding in hippocampal mossy fibers.Science. 2006; 311: 1290-1293Crossref PubMed Scopus (277) Google Scholar] recorded directly from mossy fiber boutons [6Geiger J.R. Jonas P. Dynamic control of presynaptic Ca(2+) inflow by fast-inactivating K(+) channels in hippocampal mossy fiber boutons.Neuron. 2000; 28: 927-939Abstract Full Text Full Text PDF PubMed Scopus (458) Google Scholar], several hundred microns from the soma of dentate gyrus granule cells. They found that activating synaptic input to the granule cells resulted in large subthreshold excitatory postsynaptic potentials (EPSPs) in the mossy fiber boutons, with EPSP amplitudes that were graded with stimulation intensity. They demonstrated by local application of blockers of synaptic transmission that these axonal EPSPs, which they called excitatory presynaptic potentials, or EPreSPs, are propagated from the soma and not locally generated in the axon. Thus, the axon must be capable of efficient transmission of subthreshold EPSPs down the axon. By measuring the decay of EPreSP amplitude as a function of distance from the soma, they estimated that the space constant — λ, the distance at which the voltage decays to 37% of its original value — for propagation of EPreSPs is 430 μm. Shu et al.[5Shu Y. Hasenstaub A. Duque A. Yu Y. McCormick D.A. Modulation of intracortical synaptic potentials by presynaptic somatic membrane potential.Nature. 2006; 441: 761-765Crossref PubMed Scopus (310) Google Scholar] used a novel approach to record intracellularly from axons. They noticed that the cut end of unmyelinated pyramidal cell axons in brain slices often forms a membrane ‘bleb’ which is large enough to permit whole-cell patch-clamp recording. By simultaneously recording from the soma and such axon blebs, they showed that subthreshold membrane potentials at the soma spread efficiently down the axon. In particular, spontaneous barrages of synaptic activity triggered by network ‘up’ states [7Steriade M. Timofeev I. Grenier F. Natural waking and sleep states: a view from inside neocortical neurons.J. Neurophysiol. 2001; 85: 1969-1985Crossref PubMed Scopus (912) Google Scholar] could be observed hundreds of microns down the axon (Figure 1), with a space constant λ of 417 μm. The space constant values obtained by the two studies are surprisingly large given the fine calibre of pyramidal cell and granule cell axons (typically < 1 μm), and are comparable to space constants measured in dendrites [8Larkman A.U. Major G. Stratford K.J. Jack J.J. Dendritic morphology of pyramidal neurones of the visual cortex of the rat. IV: Electrical geometry.J. Comp. Neurol. 1992; 323: 137-152Crossref PubMed Scopus (55) Google Scholar, 9Ulrich D. Stricker C. Dendrosomatic voltage and charge transfer in rat neocortical pyramidal cells in vitro.J. Neurophysiol. 2000; 84: 1445-1452Crossref PubMed Scopus (12) Google Scholar] as well as in pituitary nerve terminals [10Jackson M.B. Passive current flow and morphology in the terminal arborizations of the posterior pituitary.J. Neurophysiol. 1993; 69: 692-702Crossref PubMed Scopus (31) Google Scholar]. Given that EPreSP propagation in the axon appears to be relatively passive [4Alle H. Geiger J.R. Combined analog and action potential coding in hippocampal mossy fibers.Science. 2006; 311: 1290-1293Crossref PubMed Scopus (277) Google Scholar], this suggests that axons must have high membrane resistivity (consistent with the slow EPreSP decay) and/or relatively low intracellular resistivity, requirements confirmed by compartmental models of axons developed by both groups. Thus, two independent studies [4Alle H. Geiger J.R. Combined analog and action potential coding in hippocampal mossy fibers.Science. 2006; 311: 1290-1293Crossref PubMed Scopus (277) Google Scholar, 5Shu Y. Hasenstaub A. Duque A. Yu Y. McCormick D.A. Modulation of intracortical synaptic potentials by presynaptic somatic membrane potential.Nature. 2006; 441: 761-765Crossref PubMed Scopus (310) Google Scholar] have directly demonstrated that subthreshold synaptic potentials spread highly effectively in the axons over distances of hundreds of microns. What are the functional consequences of the efficient axonal propagation of subthreshold membrane potentials? Both groups [4Alle H. Geiger J.R. Combined analog and action potential coding in hippocampal mossy fibers.Science. 2006; 311: 1290-1293Crossref PubMed Scopus (277) Google Scholar, 5Shu Y. Hasenstaub A. Duque A. Yu Y. McCormick D.A. Modulation of intracortical synaptic potentials by presynaptic somatic membrane potential.Nature. 2006; 441: 761-765Crossref PubMed Scopus (310) Google Scholar] investigated this issue by making paired recordings from presynaptic and postsynaptic neurons and examining the effect of subthreshold potentials on synaptic transmission. Importantly, subthreshold potentials alone did not appear to be sufficient to trigger transmitter release [4Alle H. Geiger J.R. Combined analog and action potential coding in hippocampal mossy fibers.Science. 2006; 311: 1290-1293Crossref PubMed Scopus (277) Google Scholar] (although depolarization may slightly enhance the release rate of single quanta [11Glitsch M. Marty A. Presynaptic effects of NMDA in cerebellar Purkinje cells and interneurons.J. Neurosci. 1999; 19: 511-519Crossref PubMed Google Scholar, 12Katz B. Miledi R. Propagation of electric activity in motor nerve terminals.Proc. R. Soc. Lond. B. 1965; 161: 453-482Crossref PubMed Scopus (217) Google Scholar]). This stands in contrast to the direct, graded transmitter release found at some synapses in the vertebrate retina and at many invertebrate synapses. Rather, both Shu et al.[5Shu Y. Hasenstaub A. Duque A. Yu Y. McCormick D.A. Modulation of intracortical synaptic potentials by presynaptic somatic membrane potential.Nature. 2006; 441: 761-765Crossref PubMed Scopus (310) Google Scholar] and Alle and Geiger [4Alle H. Geiger J.R. Combined analog and action potential coding in hippocampal mossy fibers.Science. 2006; 311: 1290-1293Crossref PubMed Scopus (277) Google Scholar] found that the primary effect of subthreshold depolarization in the axon is to enhance transmitter release that is triggered by subsequent action potentials, producing an increase in the postsynaptic response to a presynaptic action potential. These results parallel recent work showing that synaptic transmission can be modulated by small changes in presynaptic membrane potential, applied either at the soma [13Debanne D. Guerineau N.C. Gahwiler B.H. Thompson S.M. Action-potential propagation gated by an axonal I(A)-like K+ conductance in hippocampus.Nature. 1997; 389: 286-289Crossref PubMed Scopus (226) Google Scholar] or at the synaptic boutons themselves [14Awatramani G.B. Price G.D. Trussell L.O. Modulation of transmitter release by presynaptic resting potential and background calcium levels.Neuron. 2005; 48: 109-121Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar]. Thus, rather than acting directly to trigger transmitter release, subthreshold axonal potentials appear to act in a modulatory fashion. Both groups [4Alle H. Geiger J.R. Combined analog and action potential coding in hippocampal mossy fibers.Science. 2006; 311: 1290-1293Crossref PubMed Scopus (277) Google Scholar, 5Shu Y. Hasenstaub A. Duque A. Yu Y. McCormick D.A. Modulation of intracortical synaptic potentials by presynaptic somatic membrane potential.Nature. 2006; 441: 761-765Crossref PubMed Scopus (310) Google Scholar] made some efforts to investigate the mechanism underlying this modulation. At the low frequencies tested, subthreshold membrane potentials did not appear to affect propagation fidelity of action potentials per se (compare [13Debanne D. Guerineau N.C. Gahwiler B.H. Thompson S.M. Action-potential propagation gated by an axonal I(A)-like K+ conductance in hippocampus.Nature. 1997; 389: 286-289Crossref PubMed Scopus (226) Google Scholar, 15Monsivais P. Clark B.A. Roth A. Hausser M. Determinants of action potential propagation in cerebellar Purkinje cell axons.J. Neurosci. 2005; 25: 464-472Crossref PubMed Scopus (125) Google Scholar]). However, in the two preparations, different effects of subthreshold membrane potentials on axonal action potential shape were observed. While Shu et al.[5Shu Y. Hasenstaub A. Duque A. Yu Y. McCormick D.A. Modulation of intracortical synaptic potentials by presynaptic somatic membrane potential.Nature. 2006; 441: 761-765Crossref PubMed Scopus (310) Google Scholar] showed that somatic depolarizations broaden axonal action potentials, which is in turn expected to enhance synaptic release [6Geiger J.R. Jonas P. Dynamic control of presynaptic Ca(2+) inflow by fast-inactivating K(+) channels in hippocampal mossy fiber boutons.Neuron. 2000; 28: 927-939Abstract Full Text Full Text PDF PubMed Scopus (458) Google Scholar, 16Borst J.G. Sakmann B. Effect of changes in action potential shape on calcium currents and transmitter release in a calyx-type synapse of the rat auditory brainstem.Philos. Trans. R. Soc. Lond. B. 1999; 354: 347-355Crossref PubMed Scopus (139) Google Scholar], Alle and Geiger [4Alle H. Geiger J.R. Combined analog and action potential coding in hippocampal mossy fibers.Science. 2006; 311: 1290-1293Crossref PubMed Scopus (277) Google Scholar] observed little change in action potential waveform. Another possible mechanism is an increase in resting calcium in the presynaptic bouton triggered by the subthreshold depolarization [14Awatramani G.B. Price G.D. Trussell L.O. Modulation of transmitter release by presynaptic resting potential and background calcium levels.Neuron. 2005; 48: 109-121Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar]. This was tested by loading neurons with the calcium chelator EGTA to block presynaptic calcium accumulation, which reduced the enhancement of transmission in both cell types. This indicates that subthreshold potentials in the axon can trigger calcium entry via activation of low-threshold or ‘window’ calcium currents, which can raise presynaptic calcium levels sufficiently to enhance release (although this was not shown directly in these studies). However, some enhancement still remained even in the presence of high presynaptic EGTA concentrations (10 mM), particularly at the mossy fiber bouton synapse, suggesting that there may exist an additional, calcium-independent mechanism for subthreshold depolarizations to modulate release. One possibility is that there may be a direct voltage modulation of the synaptic release machinery. Thus, there could be multiple mechanisms, some of them cell-type specific, for modulation of synaptic transmission by subthreshold axonal EPSPs. Sorting out the relative importance of these different mechanisms is sure to stimulate future research. Taken together, these studies [4Alle H. Geiger J.R. Combined analog and action potential coding in hippocampal mossy fibers.Science. 2006; 311: 1290-1293Crossref PubMed Scopus (277) Google Scholar, 5Shu Y. Hasenstaub A. Duque A. Yu Y. McCormick D.A. Modulation of intracortical synaptic potentials by presynaptic somatic membrane potential.Nature. 2006; 441: 761-765Crossref PubMed Scopus (310) Google Scholar] should prompt nothing less than a revolution of our view of signalling in axons of the mammalian central nervous system. Rather than just acting as simple digital signalling devices, axons can also act in an analog manner: they not only transmit information when the neuron has reached action potential threshold, but also signal subthreshold levels of activity in a graded manner. So even if an EPSP does not trigger an action potential, it can still influence transmission of information by spikes triggered by subsequent EPSPs. Such a hybrid model of transmission (Figure 2), in which subthreshold potentials do not directly trigger release but rather modulate subsequent action-potential driven release, is not entirely unprecedented: there exist several invertebrate systems where changing membrane potential in the presynaptic neuron has been shown to alter synaptic transmission [17Nicholls J. Wallace B.G. Modulation of transmission at an inhibitory synapse in the central nervous system of the leech.J. Physiol. 1978; 281: 157-170Crossref PubMed Scopus (66) Google Scholar, 18Shimahara T. Tauc L. Multiple interneuronal afferents to the giant cells in Aplysia.J. Physiol. 1975; 247: 299-319Crossref PubMed Scopus (43) Google Scholar, 19Shapiro E. Castellucci V.F. Kandel E.R. Presynaptic membrane potential affects transmitter release in an identified neuron in Aplysia by modulating the Ca2+ and K+ currents.Proc. Natl. Acad. Sci. USA. 1980; 77: 629-633Crossref PubMed Scopus (67) Google Scholar]. What is particularly important about the new studies [4Alle H. Geiger J.R. Combined analog and action potential coding in hippocampal mossy fibers.Science. 2006; 311: 1290-1293Crossref PubMed Scopus (277) Google Scholar, 5Shu Y. Hasenstaub A. Duque A. Yu Y. McCormick D.A. Modulation of intracortical synaptic potentials by presynaptic somatic membrane potential.Nature. 2006; 441: 761-765Crossref PubMed Scopus (310) Google Scholar] is that transient depolarizations provided by physiological stimuli (EPSPs) are capable of modulating transmission. This suggests that the timing relationship of EPSPs and succeeding action potentials will be critical [4Alle H. Geiger J.R. Combined analog and action potential coding in hippocampal mossy fibers.Science. 2006; 311: 1290-1293Crossref PubMed Scopus (277) Google Scholar], favouring potentiation of transmission in response to facilitating synaptic inputs. It also provides a mechanism for short-term memory of recent activity, where synaptic release depends on the recent history of synaptic input to the neuron. This new view has several additional interesting functional implications. EPSPs attenuate as they spread down the axon. Shu et al.[5Shu Y. Hasenstaub A. Duque A. Yu Y. McCormick D.A. Modulation of intracortical synaptic potentials by presynaptic somatic membrane potential.Nature. 2006; 441: 761-765Crossref PubMed Scopus (310) Google Scholar] performed an anatomical analysis showing that more than one hundred synapses made by the axon of cortical pyramidal neurons are within a space constant of the soma and thus will be affected by subthreshold axonal modulation. However, the magnitude of any effect of subthreshold depolarization on synaptic transmission will depend on the distance of the individual synaptic contacts from the soma: proximal synaptic contacts will be strongly influenced, and distal ones less so. It is therefore likely that there exists mixed analog/digital signalling at proximal contacts, and purely digital signalling at distal contacts. This may reflect different functional roles of proximal and distal connections. Proximal connections should be influenced more by the local network context that generated the depolarization, for example oscillations or other forms of synchrony, such that the axonal depolarization represents a form of positive feedback for coordinating local networks. On the other hand, long-range connections exhibit entirely digital signalling, since local feedback is not necessary. There are many questions left open by these two remarkably complementary papers [4Alle H. Geiger J.R. Combined analog and action potential coding in hippocampal mossy fibers.Science. 2006; 311: 1290-1293Crossref PubMed Scopus (277) Google Scholar, 5Shu Y. Hasenstaub A. Duque A. Yu Y. McCormick D.A. Modulation of intracortical synaptic potentials by presynaptic somatic membrane potential.Nature. 2006; 441: 761-765Crossref PubMed Scopus (310) Google Scholar]. Firstly, how general are these findings? Both studies recorded from the large, main trunk of unmyelinated axons exhibiting relatively small amounts of branching. In axons exhibiting more branching (such as many interneuron axons), or in thinner axons (particularly axon collaterals) attenuation of subthreshold potentials should be much steeper, and so will permit less hybrid signalling. It also remains to be determined how well subthreshold potentials can spread in myelinated axons. Secondly, can inhibitory postsynaptic potentials (IPSPs) spread down the axon with similar efficacy to EPSPs, and if so, how do IPSPs influence synaptic release? Thirdly, how do axonal voltage-gated channels influence propagation? Alle and Geiger [4Alle H. Geiger J.R. Combined analog and action potential coding in hippocampal mossy fibers.Science. 2006; 311: 1290-1293Crossref PubMed Scopus (277) Google Scholar] showed that application of the sodium channel blocker tetrodotoxin had only a relatively small effect on the EPreSP amplitude; however, the dependence on EPreSP amplitude was not examined, and other channels may also contribute (particularly Ih cation channels and also calcium channels, as expected from the fact that subthreshold calcium entry appears to influence action potential-dependent release). Fourthly, as action potential propagation itself can be modulated by membrane potential [13Debanne D. Guerineau N.C. Gahwiler B.H. Thompson S.M. Action-potential propagation gated by an axonal I(A)-like K+ conductance in hippocampus.Nature. 1997; 389: 286-289Crossref PubMed Scopus (226) Google Scholar, 15Monsivais P. Clark B.A. Roth A. Hausser M. Determinants of action potential propagation in cerebellar Purkinje cell axons.J. Neurosci. 2005; 25: 464-472Crossref PubMed Scopus (125) Google Scholar], it is conceivable that synaptic potentials spreading in the axon can either promote or inhibit propagation in different regions of the axon. And lastly, if axo-axonic synapses are able to trigger presynaptic potentials, the present studies suggest that these potentials should be able to spread to other synapses to influence synaptic release, or even retrogradely to influence action potential propagation or initiation. Such two-way traffic of subthreshold potentials in the axon may have unexpected consequences for information processing. The new studies [4Alle H. Geiger J.R. Combined analog and action potential coding in hippocampal mossy fibers.Science. 2006; 311: 1290-1293Crossref PubMed Scopus (277) Google Scholar, 5Shu Y. Hasenstaub A. Duque A. Yu Y. McCormick D.A. Modulation of intracortical synaptic potentials by presynaptic somatic membrane potential.Nature. 2006; 441: 761-765Crossref PubMed Scopus (310) Google Scholar] should provide a major stimulus to the growing recent change in perspective on axons as signalling devices [20Debanne D. Information processing in the axon.Nat. Rev. Neurosci. 2004; 5: 304-316Crossref PubMed Scopus (291) Google Scholar]. Rather than acting as simple, reliable transmission lines for action potentials, axons have now been shown to exhibit a rich repertoire of behaviour, in which both action potentials and synaptic potentials can be transmitted to synapses, and can interact to modulate synaptic release. This suggests that the action potential initiation site is no longer the final site of synaptic integration, but that action potentials and synaptic potentials continue to interact along the length of the axon. The next step will be to understand the computational significance of these interactions and how they can be exploited to enhance the normal functioning of the mammalian central nervous system. Now that the axons of mammalian neurons are finally becoming accessible to direct investigation using both imaging and electrophysiological techniques, we can expect many more breakthroughs from these tiny structures." @default.
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• W1963878275 title "Neural Coding: Hybrid Analog and Digital Signalling in Axons" @default.
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