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Enhancing the fidelity of neurotransmission by activity-dependent facilitation of presynaptic potassium currents.

Yang YM, Wang W, Fedchyshyn MJ, Zhou Z, Ding J, Wang LY - Nat Commun (2014)

Bottom Line: Experimental evidence and computer simulations demonstrate that this facilitation originates from dynamic transition of intermediate gating states of voltage-gated K(+) channels (Kvs), and specifically attenuates spike amplitude and inter-spike potential during high-frequency firing.Single or paired recordings from a mammalian central synapse further reveal that facilitation of Kvs constrains presynaptic Ca(2+) influx, thereby efficiently allocating SVs in the RRP to drive postsynaptic spiking at high rates.We conclude that presynaptic Kv facilitation imparts neurons with a powerful control of transmitter release to dynamically support high-fidelity neurotransmission.

View Article: PubMed Central - PubMed

Affiliation: 1] Program in Neurosciences and Mental Health, SickKids Research Institute, Toronto, Ontario, Canada M5G 1X8 [2] Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8 [3].

ABSTRACT
Neurons convey information in bursts of spikes across chemical synapses where the fidelity of information transfer critically depends on synaptic input-output relationship. With a limited number of synaptic vesicles (SVs) in the readily releasable pool (RRP), how nerve terminals sustain transmitter release during intense activity remains poorly understood. Here we report that presynaptic K(+) currents evoked by spikes facilitate in a Ca(2+)-independent but frequency- and voltage-dependent manner. Experimental evidence and computer simulations demonstrate that this facilitation originates from dynamic transition of intermediate gating states of voltage-gated K(+) channels (Kvs), and specifically attenuates spike amplitude and inter-spike potential during high-frequency firing. Single or paired recordings from a mammalian central synapse further reveal that facilitation of Kvs constrains presynaptic Ca(2+) influx, thereby efficiently allocating SVs in the RRP to drive postsynaptic spiking at high rates. We conclude that presynaptic Kv facilitation imparts neurons with a powerful control of transmitter release to dynamically support high-fidelity neurotransmission.

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Computer simulation of gating kinetics of Kvs(a, b) IK recorded from an outside-out patch of the calyx of Held nerve terminal (a) or simulated by a computational model containing five closed states and one open state (b) in response to depolarization steps from −120 to 40 mV with (magenta traces, middle panels) or without (black traces, top panels) a preceding AP-like ramp (amplitude: 120 mV; half-width: 0.45 ms). The amplitude of IK at 2 ms after the start of voltage steps is plotted against step potentials (bottom panels) to illustrate the early activation of Kvs by the preceding depolarization. (c), Example of simulated IK (middle) in response to a paired-pulse protocol (spike amplitude: 110 mV and half-width: 0.45 ms, paired-pulse interval: 1.5–6 ms; top). The magnitude and frequency-dependence of Kv facilitation are well reminiscent of experimental recordings of IK as shown in Figure 1. Based on the simulation model (see Table 1) with all the six states summated to 1 at any given time point during the paired-pulse paradigm, probabilities for each state of K-LT at the onset of the 1st or 2nd spikes are plotted against various inter-pulse intervals (bottom).
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Figure 5: Computer simulation of gating kinetics of Kvs(a, b) IK recorded from an outside-out patch of the calyx of Held nerve terminal (a) or simulated by a computational model containing five closed states and one open state (b) in response to depolarization steps from −120 to 40 mV with (magenta traces, middle panels) or without (black traces, top panels) a preceding AP-like ramp (amplitude: 120 mV; half-width: 0.45 ms). The amplitude of IK at 2 ms after the start of voltage steps is plotted against step potentials (bottom panels) to illustrate the early activation of Kvs by the preceding depolarization. (c), Example of simulated IK (middle) in response to a paired-pulse protocol (spike amplitude: 110 mV and half-width: 0.45 ms, paired-pulse interval: 1.5–6 ms; top). The magnitude and frequency-dependence of Kv facilitation are well reminiscent of experimental recordings of IK as shown in Figure 1. Based on the simulation model (see Table 1) with all the six states summated to 1 at any given time point during the paired-pulse paradigm, probabilities for each state of K-LT at the onset of the 1st or 2nd spikes are plotted against various inter-pulse intervals (bottom).

Mentions: Given that both native and recombinant Kvs exhibit activity-dependent facilitation, we postulated that this functional phenotype could reside in intrinsic gating kinetics of these channels. To test this, we first fit activation and deactivation kinetics of IK-HT and IK-LT recorded from the outside-out calyceal patches with the Markov modeling to derive gating rate constants 14–16. We found that the classic 6-state linear gating scheme (C0, C1, C2, C3, C4, O) fit experimental data well, and more importantly recapitulated the major characteristics of these native currents. For instance, IK-LT predicted by the model closely resembled the recorded currents in the lower activation threshold of IK following a preceding spike and paired-pulse induced facilitation (Fig. 5a–c). Model fittings revealed that the backward transition rate constant (β) of K-LT was significantly slower than that of K-HT while the forward rate constants (α) for both subtypes of Kvs were comparable (Table 1), indicating that slower return from the intermediate closed states (C4…C1) to resting closed state (C0) may be associated with more robust facilitation of IK-LT. Indeed, when we plotted probabilities of all the kinetic states at equilibrium before the 1st spikes during the paired-pulse paradigm, we found that K-LT largely stayed in the C0 and C1 states with the other states being less dominant. The same analysis at the onset of the 2nd pulses showed that the probability for the C4 or O state of K-LT was very low and the C1 state remained relatively constant at varied inter-pulse intervals. By contrast, the distribution of other closed states was highly sensitive to the intervals. As the interval was shortened (e.g. < 5ms), the probability of the channel remaining in the intermediate states (C2 and C3) steeply increased at the expense of lowering the probability for the resting closed state (C0). This dramatic re-distribution of different closed states well correlated with the time course of IK-LT facilitation (Fig. 5c). Taken together, we interpret our experimental and simulation results as such that the intermediate closed states of Kvs arising from previous activity decrease energy barrier to reach the open state and hence account for accelerated activation and lowered activation threshold for Kvs susceptible to subsequent stimuli.


Enhancing the fidelity of neurotransmission by activity-dependent facilitation of presynaptic potassium currents.

Yang YM, Wang W, Fedchyshyn MJ, Zhou Z, Ding J, Wang LY - Nat Commun (2014)

Computer simulation of gating kinetics of Kvs(a, b) IK recorded from an outside-out patch of the calyx of Held nerve terminal (a) or simulated by a computational model containing five closed states and one open state (b) in response to depolarization steps from −120 to 40 mV with (magenta traces, middle panels) or without (black traces, top panels) a preceding AP-like ramp (amplitude: 120 mV; half-width: 0.45 ms). The amplitude of IK at 2 ms after the start of voltage steps is plotted against step potentials (bottom panels) to illustrate the early activation of Kvs by the preceding depolarization. (c), Example of simulated IK (middle) in response to a paired-pulse protocol (spike amplitude: 110 mV and half-width: 0.45 ms, paired-pulse interval: 1.5–6 ms; top). The magnitude and frequency-dependence of Kv facilitation are well reminiscent of experimental recordings of IK as shown in Figure 1. Based on the simulation model (see Table 1) with all the six states summated to 1 at any given time point during the paired-pulse paradigm, probabilities for each state of K-LT at the onset of the 1st or 2nd spikes are plotted against various inter-pulse intervals (bottom).
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Related In: Results  -  Collection

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Figure 5: Computer simulation of gating kinetics of Kvs(a, b) IK recorded from an outside-out patch of the calyx of Held nerve terminal (a) or simulated by a computational model containing five closed states and one open state (b) in response to depolarization steps from −120 to 40 mV with (magenta traces, middle panels) or without (black traces, top panels) a preceding AP-like ramp (amplitude: 120 mV; half-width: 0.45 ms). The amplitude of IK at 2 ms after the start of voltage steps is plotted against step potentials (bottom panels) to illustrate the early activation of Kvs by the preceding depolarization. (c), Example of simulated IK (middle) in response to a paired-pulse protocol (spike amplitude: 110 mV and half-width: 0.45 ms, paired-pulse interval: 1.5–6 ms; top). The magnitude and frequency-dependence of Kv facilitation are well reminiscent of experimental recordings of IK as shown in Figure 1. Based on the simulation model (see Table 1) with all the six states summated to 1 at any given time point during the paired-pulse paradigm, probabilities for each state of K-LT at the onset of the 1st or 2nd spikes are plotted against various inter-pulse intervals (bottom).
Mentions: Given that both native and recombinant Kvs exhibit activity-dependent facilitation, we postulated that this functional phenotype could reside in intrinsic gating kinetics of these channels. To test this, we first fit activation and deactivation kinetics of IK-HT and IK-LT recorded from the outside-out calyceal patches with the Markov modeling to derive gating rate constants 14–16. We found that the classic 6-state linear gating scheme (C0, C1, C2, C3, C4, O) fit experimental data well, and more importantly recapitulated the major characteristics of these native currents. For instance, IK-LT predicted by the model closely resembled the recorded currents in the lower activation threshold of IK following a preceding spike and paired-pulse induced facilitation (Fig. 5a–c). Model fittings revealed that the backward transition rate constant (β) of K-LT was significantly slower than that of K-HT while the forward rate constants (α) for both subtypes of Kvs were comparable (Table 1), indicating that slower return from the intermediate closed states (C4…C1) to resting closed state (C0) may be associated with more robust facilitation of IK-LT. Indeed, when we plotted probabilities of all the kinetic states at equilibrium before the 1st spikes during the paired-pulse paradigm, we found that K-LT largely stayed in the C0 and C1 states with the other states being less dominant. The same analysis at the onset of the 2nd pulses showed that the probability for the C4 or O state of K-LT was very low and the C1 state remained relatively constant at varied inter-pulse intervals. By contrast, the distribution of other closed states was highly sensitive to the intervals. As the interval was shortened (e.g. < 5ms), the probability of the channel remaining in the intermediate states (C2 and C3) steeply increased at the expense of lowering the probability for the resting closed state (C0). This dramatic re-distribution of different closed states well correlated with the time course of IK-LT facilitation (Fig. 5c). Taken together, we interpret our experimental and simulation results as such that the intermediate closed states of Kvs arising from previous activity decrease energy barrier to reach the open state and hence account for accelerated activation and lowered activation threshold for Kvs susceptible to subsequent stimuli.

Bottom Line: Experimental evidence and computer simulations demonstrate that this facilitation originates from dynamic transition of intermediate gating states of voltage-gated K(+) channels (Kvs), and specifically attenuates spike amplitude and inter-spike potential during high-frequency firing.Single or paired recordings from a mammalian central synapse further reveal that facilitation of Kvs constrains presynaptic Ca(2+) influx, thereby efficiently allocating SVs in the RRP to drive postsynaptic spiking at high rates.We conclude that presynaptic Kv facilitation imparts neurons with a powerful control of transmitter release to dynamically support high-fidelity neurotransmission.

View Article: PubMed Central - PubMed

Affiliation: 1] Program in Neurosciences and Mental Health, SickKids Research Institute, Toronto, Ontario, Canada M5G 1X8 [2] Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8 [3].

ABSTRACT
Neurons convey information in bursts of spikes across chemical synapses where the fidelity of information transfer critically depends on synaptic input-output relationship. With a limited number of synaptic vesicles (SVs) in the readily releasable pool (RRP), how nerve terminals sustain transmitter release during intense activity remains poorly understood. Here we report that presynaptic K(+) currents evoked by spikes facilitate in a Ca(2+)-independent but frequency- and voltage-dependent manner. Experimental evidence and computer simulations demonstrate that this facilitation originates from dynamic transition of intermediate gating states of voltage-gated K(+) channels (Kvs), and specifically attenuates spike amplitude and inter-spike potential during high-frequency firing. Single or paired recordings from a mammalian central synapse further reveal that facilitation of Kvs constrains presynaptic Ca(2+) influx, thereby efficiently allocating SVs in the RRP to drive postsynaptic spiking at high rates. We conclude that presynaptic Kv facilitation imparts neurons with a powerful control of transmitter release to dynamically support high-fidelity neurotransmission.

Show MeSH
Related in: MedlinePlus