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The effects of depolarization, repolarization and amplitude of an AP on the timing of presynaptic Ca 2+ entry. (a-c) Examples of I Ca (bottom panels) in response to three sets of AP-like voltage ramps (top panels) from −80 to 40 mV: AP-DEP (depolarization time from 0.2 to 1.0 ms with 0.1 ms increments, repolarization time 0.4 ms, a), AP-REP (depolarization time 0.2 ms, repolarization time from 0.2 to 1.6 ms with 0.2 ms increments, b), and AP-STEP (depolarization and repolarization time 0.2 ms, plateau duration from 0.1 to 0.9 ms with 0.1 ms increments, c). (d) Diagram showing the definition of time zero as the end of repolarization phase in the three pseudo-AP protocols. (e) The relative time (Δt) between time zero and the starting point of I Ca was measured and plotted against the duration of depolarization (AP-DEP, open diamonds, n = 4), repolarization (AP-REP, filled squares, n = 4) and plateau step (AP-STEP, open triangles, n = 4), respectively. (f) I Ca (middle panel) generated by a series of AP-like voltage paradigms (top panel) with increasing amplitude from 80 to 130 mV (depolarization time 0.3 ms, repolarization time 0.6 ms). In the bottom panel, the dotted line was a normalized trace of the first I Ca to the last one, showing their different peak time. (g-i) Summary plots of
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The waveform of presynaptic action potentials (APs) regulates the magnitude of Ca2+ currents (ICa) and neurotransmitter release. However, how APs control the timing of synaptic transmission remains unclear. Using the calyx of Held synapse, we find that Na+ and K+ channels affect the timing by changing the AP waveform. Specifically, the onset of ICa...
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... presynaptic Ca 2+ influx (Figs 1 and 2). To circumvent the complicate properties of Na + and K + channel blockers, we designed three sets of AP-like voltage clamp commands with the same amplitude, i.e. AP-DEP, AP-REP and AP-STEP, which referred to the specific changes in the depolarization, repolarization and plateau duration of APs, respectively (Fig. 3a-c, top panels). In response to the three paradigms, the amplitude of I Ca increased as the AP width was broadened and eventually saturated, as previously described 10 . When the time interval (Δt) between the end point of AP repolarization phase (time zero, t(0)) and the start point of I Ca was quantified (Fig. 3d), we found that I Ca ...
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... duration of APs, respectively (Fig. 3a-c, top panels). In response to the three paradigms, the amplitude of I Ca increased as the AP width was broadened and eventually saturated, as previously described 10 . When the time interval (Δt) between the end point of AP repolarization phase (time zero, t(0)) and the start point of I Ca was quantified (Fig. 3d), we found that I Ca were essentially tail currents for AP-DEP and AP-STEP paradigms (Fig. 3a,c). This indicated that Ca 2+ entry took place near the end of the repolarization phase of APs with a Δt of ~0.2 ms or less, independent of the depolarization or step duration (Fig. 3e). However, I Ca evoked by the AP-REP protocol were ...
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... the amplitude of I Ca increased as the AP width was broadened and eventually saturated, as previously described 10 . When the time interval (Δt) between the end point of AP repolarization phase (time zero, t(0)) and the start point of I Ca was quantified (Fig. 3d), we found that I Ca were essentially tail currents for AP-DEP and AP-STEP paradigms (Fig. 3a,c). This indicated that Ca 2+ entry took place near the end of the repolarization phase of APs with a Δt of ~0.2 ms or less, independent of the depolarization or step duration (Fig. 3e). However, I Ca evoked by the AP-REP protocol were initially tail currents when the repolarization time was short (Fig. 3b). As the repolarization time was ...
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... phase (time zero, t(0)) and the start point of I Ca was quantified (Fig. 3d), we found that I Ca were essentially tail currents for AP-DEP and AP-STEP paradigms (Fig. 3a,c). This indicated that Ca 2+ entry took place near the end of the repolarization phase of APs with a Δt of ~0.2 ms or less, independent of the depolarization or step duration (Fig. 3e). However, I Ca evoked by the AP-REP protocol were initially tail currents when the repolarization time was short (Fig. 3b). As the repolarization time was prolonged, the onset of I Ca advanced towards the early part of AP repolarization phase and appeared as Figure 1. The contribution of presynaptic K + channels to the onset of I Ca ...
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... for AP-DEP and AP-STEP paradigms (Fig. 3a,c). This indicated that Ca 2+ entry took place near the end of the repolarization phase of APs with a Δt of ~0.2 ms or less, independent of the depolarization or step duration (Fig. 3e). However, I Ca evoked by the AP-REP protocol were initially tail currents when the repolarization time was short (Fig. 3b). As the repolarization time was prolonged, the onset of I Ca advanced towards the early part of AP repolarization phase and appeared as Figure 1. The contribution of presynaptic K + channels to the onset of I Ca and EPSC. (a,b) A representative AP (top panels) and EPSC (bottom panels) recorded from pre-and postsynaptic compartments of ...
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... www.nature.com/scientificreports/ typical off currents, in parallel with changes in the amplitude and kinetics of I Ca . When Δt was plotted against the duration of AP repolarization, Δt linearly shifted to the negative values as the repolarization was extended (Fig. 3e). For instance, Δt changed from −0.21 ± 0.01 ms for 0.4 ms of repolarization time to −1.27 ± 0.04 ms for 1.6 ms of repolarization time. These results demonstrate that the timing of Ca 2+ influx into the nerve terminal is dependent on the time course of AP repolarization but not depolarization, consistent with the effect of TEA on the ...
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... By applying a series of pseudo-APs with the same depolarization and repolar- ization time yet varied amplitude, ranging from 80 to 130 mV (Fig. 3f, top panel) to evoke I Ca , we found that increasing the AP amplitude raised the size of I Ca (from 0.41 ± 0.06 nA for 80 mV to 1.39 ± 0.15 nA for 130 mV of APs) and delayed the peak time of I Ca (from −0.09 ± 0.01 ms for 80 mV to 0.05 ± 0.005 ms for 130 mV of APs, Fig. 3h), with a marginal effect on the onset timing of I Ca (−0.40 ± ...
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... and repolar- ization time yet varied amplitude, ranging from 80 to 130 mV (Fig. 3f, top panel) to evoke I Ca , we found that increasing the AP amplitude raised the size of I Ca (from 0.41 ± 0.06 nA for 80 mV to 1.39 ± 0.15 nA for 130 mV of APs) and delayed the peak time of I Ca (from −0.09 ± 0.01 ms for 80 mV to 0.05 ± 0.005 ms for 130 mV of APs, Fig. 3h), with a marginal effect on the onset timing of I Ca (−0.40 ± 0.01 ms and −0.37 ± 0.01 ms for 80 mV and 130 mV of APs, respectively, Fig. 3g). Further analysis on the kinetics of evoked I Ca showed that the rise time of I Ca was slowed (from 0.19 ± 0.003 ms for 80 mV to 0.28 ± 0.01 ms for 130 mV of APs), while the decay time of I Ca ...
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... amplitude raised the size of I Ca (from 0.41 ± 0.06 nA for 80 mV to 1.39 ± 0.15 nA for 130 mV of APs) and delayed the peak time of I Ca (from −0.09 ± 0.01 ms for 80 mV to 0.05 ± 0.005 ms for 130 mV of APs, Fig. 3h), with a marginal effect on the onset timing of I Ca (−0.40 ± 0.01 ms and −0.37 ± 0.01 ms for 80 mV and 130 mV of APs, respectively, Fig. 3g). Further analysis on the kinetics of evoked I Ca showed that the rise time of I Ca was slowed (from 0.19 ± 0.003 ms for 80 mV to 0.28 ± 0.01 ms for 130 mV of APs), while the decay time of I Ca remained the same (0.32 ± 0.04 ms for 80 mV vs 0.31 ± 0.08 ms for 130 mV of APs, Fig. 3i), indicating that the AP Figure 2. The contribution of ...
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... ms and −0.37 ± 0.01 ms for 80 mV and 130 mV of APs, respectively, Fig. 3g). Further analysis on the kinetics of evoked I Ca showed that the rise time of I Ca was slowed (from 0.19 ± 0.003 ms for 80 mV to 0.28 ± 0.01 ms for 130 mV of APs), while the decay time of I Ca remained the same (0.32 ± 0.04 ms for 80 mV vs 0.31 ± 0.08 ms for 130 mV of APs, Fig. 3i), indicating that the AP Figure 2. The contribution of presynaptic Na + channels to the onset of I Ca and EPSC. (a,b) A representative AP (top panels) and EPSC (bottom panels) recorded from pre-and postsynaptic compartments of the calyx of Held synapse in response to axonal stimulation (blue bars) applied to a brain slice taken from a ...
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... (AP I ) and mature (AP M ) calyces 10 as templates to evoke I Ca . Conjointly, two pseudo-APs with the comparable halfwidth were applied to the same terminals (Fig. 4b). In all cases, the timing of inward I Ca fell in the repolarization phase with their onset shifting forward to the peak for wider APs. This shift was expected as demonstrated in Fig. 3 ...
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... the magnitude of I Ca evoked by real and pseudo-APs increases with prolonged depolarization and repolarization periods, the onset timing of I Ca is exclusively determined by the repolarization rates (Fig. 3). The amplitude of APs and [Ca 2+ ] e also have profound impact on the size and peak time of I Ca but not their onset tim- ing (Figs 3 and 4). Ca 2+ influx evoked by physiological APs begins during or near the end of the repolarization phase referred as off or tail currents (Figs 1, 2, 4, 5 and 8). When the AP waveform broadens, as ...
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... the magnitude of I Ca evoked by real and pseudo-APs increases with prolonged depolarization and repolarization periods, the onset timing of I Ca is exclusively determined by the repolarization rates (Fig. 3). The amplitude of APs and [Ca 2+ ] e also have profound impact on the size and peak time of I Ca but not their onset tim- ing (Figs 3 and 4). Ca 2+ influx evoked by physiological APs begins during or near the end of the repolarization phase referred as off or tail currents (Figs 1, 2, 4, 5 and 8). ...
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... Consequently, the fast voltage signals such as the action potentials (APs) are particularly vulnerable to signal distortion associated with direct recordings in small axonal structures. The shape of axonal APs is a key determinant of neuronal signaling that affects neurotransmitter release and short-term dynamics in synaptic connections (Katz and Miledi, 1967;Borst and Sakmann, 1999;Geiger and Jonas, 2000;Bean, 2007;Kawaguchi and Sakaba, 2015;Chao and Yang, 2019;Zbili and Debanne, 2019). This synaptic activity generates dynamic changes in the postsynaptic membrane potential that would be translated into AP firing of the postsynaptic neuron (Koch and Segev, 2000;London and Häusser, 2005;Silver, 2010). ...
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... We find that PSP latency is weakly correlated with action potential width for excitatory (r 2 =0.05, p=1.71e -05 ) synapses and more strongly correlated for inhibitory synapses (r 2 =0.19, p=1.15e -49 ). The stronger correlation in inhibitory synapses likely reflects that the calcium entry that drives release occurs during action potential repolarization when the driving force is high and the calcium channels are in the act of closing (Chao and Yang, 2019), whereas at excitatory synapses, there may be appreciable calcium entry during the action potential. As our data was acquired at near physiological temperature, the observed latencies in this study may be considered to reasonably reflect in-vivo timing. ...
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... presynaptic SNARE complex and vesicle priming processes, and accelerated endocytic membrane retrieval [56][57][58]. ...
Numerous neuronal properties including the synaptic vesicle release process, neurotransmitter receptor complement, and postsynaptic ion channels are involved in transforming synaptic inputs into postsynaptic spiking. Temperature is a significant influencer of neuronal function and synaptic integration. Changing temperature can affect neuronal physiology in a diversity of ways depending on how it affects different members of the cell’s ion channel complement. Temperature’s effects on neuronal function are critical for pathological states such as fever, which can trigger seizure activity, but are also important in interpreting and comparing results of experiments conducted at room vs physiological temperature. The goal of this study was to examine the influence of temperature on synaptic properties and ion channel function in thalamocortical (TC) relay neurons in acute brain slices of the dorsal lateral geniculate nucleus, a key synaptic target of retinal ganglion cells in the thalamus. Warming the superfusate in patch clamp experiments with acutely-prepared brain slices led to an overall inhibition of synaptically-driven spiking behavior in TC neurons in response to a retinal ganglion cell spike train. Further study revealed that this was associated with an increase in presynaptic synaptic vesicle release probability and synaptic depression and altered passive and active membrane properties. Additionally, warming the superfusate triggered activation of an inwardly rectifying potassium current and altered the voltage-dependence of voltage-gated Na⁺ currents and T-type calcium currents. This study highlights the importance of careful temperature control in ex vivo physiological experiments and illustrates how numerous properties such as synaptic inputs, active conductances, and passive membrane properties converge to determine spike output.
... In endothermic animals at physiological temperatures, Ca 2+ channel-opening kinetics are much faster. The increased driving force on the repolarising phase of the action potential is associated with larger currents, but significant Ca 2+ influx can occur on the rising limb of the action potential and transmitter release can begin before the action potential terminates (Sabatini and Regehr, 1999;Chao and Yang, 2019). Another consequence of the slow forward rate of Ca 2+ channel opening relative to the depolarising phase of the action potential is that only a fraction (approximately 10% or less) of the available channels are normally opened by an action potential. ...
Information is coded in the brain as patterns of electrical impulses that are transmitted along nerve processes. These impulses are passed from one neuron to the next primarily at chemical synapses where the electrical event is converted to the release of a neurotransmitter substance that activates the next neuron in the pathway. Neurotransmitter release is triggered by the opening of ‘voltage‐sensitive’ calcium channels, the admission of a small pulse of Ca ²⁺ ions and the binding of these ions to the neurotransmitter secretion apparatus culminating in the fusion and discharge of a transmitter‐filled secretory vesicle. Increasing evidence suggests that most synapses an individual release site is gated by ion influx through one or more nearby calcium channels. In this section, we explore the physiology of this impulse‐to‐secretion gating mechanism.
Key Concepts
Information is transmitted between one neuron and the next at synapses where the nerve fibre terminal of the upstream (presynaptic) neuron contacts the surface membrane of the downstream (postsynaptic) one.
Most synapses transmit by secreting a chemical neurotransmitter across the narrow space between pre‐ and postsynaptic surface membranes.
Transmitter secretion is triggered by an electrical impulse that travels down the presynaptic nerve fibre to the terminal.
Neurotransmitter is stored in tiny membrane ‘packets’ called synaptic vesicles which can be triggered to secrete by fusing with the presynaptic membrane at the ‘transmitter release site’.
The synaptic vesicles are ‘docked’ at the release site ready for secretion.
Influx of calcium ions through selective voltage‐sensitive ion channels (calcium channels) plays a key role to link the action potential to the triggering of secretory vesicle discharge.
Calcium channels are positioned very close to the secretory vesicles so that when they open the spurt of entering calcium ions, called a ‘calcium domain’, can rapidly and effectively access the triggering sites for synaptic vesicle fusion.
Patch-clamp instruments including amplifier circuits and pipettes affect the recorded voltage signals. We hypothesized that realistic and complete in silico representation of recording instruments together with detailed morphology and biophysics of small recorded structures will precisely reveal signal distortions and provides a tool that predicts native signals from distorted voltage recordings. Therefore, we built a model that was verified by small axonal recordings. The model accurately recreated actual action potential measurements with typical recording artefacts and predicted the native electrical behavior. The simulations verified that recording instruments substantially filter voltage recordings. Moreover, we revealed that instrumentation directly interferes with local signal generation depending on the size of the recorded structures, which complicates the interpretation of recordings from smaller structures, such as axons. However, our model offers a straightforward approach that predicts the native waveforms of fast voltage signals and the underlying conductances even from the smallest neuronal structures.
Information is coded in the brain as patterns of electrical impulses that are transmitted along nerve processes. These impulses are passed from one neuron to the next primarily at chemical synapses where the electrical event is converted to the release of a neurotransmitter substance that activates the next neuron in the pathway. Neurotransmitter release is triggered by the opening of ‘voltage‐sensitive’ calcium channels, the admission of a pulse of Ca²⁺ ions and the binding of these ions to the neurotransmitter secretion apparatus culminating in the fusion and discharge of a transmitter‐filled secretory vesicle. Increasing evidence suggests that at many synapses an individual release site is gated by ion influx through one or a few nearby calcium channels while at others Ca²⁺ from many channels summates to drive release. In this section, we explore the physiology of this impulse‐to‐secretion gating mechanism.
Key Concepts
• Information is transmitted between one neuron and the next at synapses where an upstream (presynaptic) neuron interacts with the membrane of the downstream (postsynaptic) one.
• Synapses transmit by secreting a chemical neurotransmitter, often across a narrow space (cleft) between pre‐ and postsynaptic surface membranes.
• Most neurotransmitters are stored in tiny membrane ‘packets’ called synaptic vesicles which can be triggered to secrete by fusing with the presynaptic membrane.
• The synaptic vesicles are ‘docked’ at the release site ready for secretion which is dependent upon a large local increase in [Ca²⁺].
• Transmitter secretion is triggered by an electrical impulse that travels down the presynaptic axon or into a dendrite to release sites.
• Influx of calcium ions through Ca²⁺ selective, voltage‐sensitive ion channels links the voltage transient of the action potential to the triggering of secretory vesicle discharge.
• Ca²⁺ channels are positioned very close to the secretory vesicles so that when they open the spurt of entering Ca²⁺ ions, called a ‘calcium domain’, can rapidly and effectively access the triggering sites for synaptic vesicle fusion.
