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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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Related in: MedlinePlus

Mechanisms underlying Kv facilitation from recombinant Kv channels(a, b) IK (bottom panels) generated from CHO cells expressing Kv3.1 (blue, a) or Kv1.1&1.2 channels (magenta, b) by paired-pulse stimulation protocol (AP waveform: −90 to +100 mV, rise time: 0.3 ms, decay time: 0.6 ms, paired-pulse interval: 1 to 8 ms with increment of 0.5 ms, top panels). (c) PPF in the area integral of IK is summarized for CHO cells transfected with Kv3.1 (blue circles, n=8) or Kv1.1&1.2 (magenta circles, n=6) constructs. The solid lines are fits to a single exponential function and time constants are shown in the figure. (d–f) The first pair of IK in a are focused to show the time difference (Δt) between the peak of APs and that of corresponding IK (d). Note the dramatic early onset of the 2nd IK compared to the 1st IK. Quantitative analysis of Δt are demonstrated for expression of Kv3.1 (n=8, e) or Kv1.1&1.2 (n=6, f). (g–j) Voltage steps from −120 to 20 mV (10 ms long, top panels) applied to elicit IK from a CHO cell expressing Kv3.1 (middle panels) or Kv1.1&1.2 (bottom panels) with (h) or without (g) the pre-pulse (−120 to 100 mV, rise time: 0.3 ms, decay time: 0.6 ms). The amplitude of IK at varied potentials, measured at 2 ms after beginning of depolarization steps (dotted lines), is plotted in i (Kv3.1, n=4) and j (Kv1.1&1.2, n=4). Error bars indicate ± s.e.m.
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Figure 4: Mechanisms underlying Kv facilitation from recombinant Kv channels(a, b) IK (bottom panels) generated from CHO cells expressing Kv3.1 (blue, a) or Kv1.1&1.2 channels (magenta, b) by paired-pulse stimulation protocol (AP waveform: −90 to +100 mV, rise time: 0.3 ms, decay time: 0.6 ms, paired-pulse interval: 1 to 8 ms with increment of 0.5 ms, top panels). (c) PPF in the area integral of IK is summarized for CHO cells transfected with Kv3.1 (blue circles, n=8) or Kv1.1&1.2 (magenta circles, n=6) constructs. The solid lines are fits to a single exponential function and time constants are shown in the figure. (d–f) The first pair of IK in a are focused to show the time difference (Δt) between the peak of APs and that of corresponding IK (d). Note the dramatic early onset of the 2nd IK compared to the 1st IK. Quantitative analysis of Δt are demonstrated for expression of Kv3.1 (n=8, e) or Kv1.1&1.2 (n=6, f). (g–j) Voltage steps from −120 to 20 mV (10 ms long, top panels) applied to elicit IK from a CHO cell expressing Kv3.1 (middle panels) or Kv1.1&1.2 (bottom panels) with (h) or without (g) the pre-pulse (−120 to 100 mV, rise time: 0.3 ms, decay time: 0.6 ms). The amplitude of IK at varied potentials, measured at 2 ms after beginning of depolarization steps (dotted lines), is plotted in i (Kv3.1, n=4) and j (Kv1.1&1.2, n=4). Error bars indicate ± s.e.m.

Mentions: To explore the mechanisms underlying heterogeneity in KvF, we did paired-pulse experiments in CHO cell lines expressing recombinant homomeric Kv3.1 or heteromeric Kv1.1&1.2 channels, which constituted the major subunits of native Kvs 18, 19, 21–23 in the calyx of Held synapse. Simple spherical morphology of CHO cells also ensured accurate measurement of IK with minimal space-clamp errors. We found that the PPF in Kv1.1&1.2 currents was more robust (e.g. PPF for Kv1.1&1.2: 495.5±55.8% vs. for Kv3.1: 389.4±31.8% at the interval of 1 ms) and decayed much slower with increased inter-spike intervals than that in Kv3.1 currents (τ=1.0 ms for Kv1.1&1.2 vs. τ=0.4 ms for Kv3.1, Fig. 4a–c), in line with the observations from native IK-HT and IK-LT in the nerve terminal (Fig. 1). Most notably, the temporal onset of IK evoked by the 2nd spikes was shifted towards to the early phase of the pseudo-spikes, as quantified by the time difference between the peak of APs and that of their evoked IK (Fig. 4d). The timing shift of the 2nd IK declined exponentially over prolonged inter-spike intervals with the comparable time constants (Kv3.1: 0.4 ms vs. Kv1.1&1.2: 2.4 ms, Fig. 4e,f) to those of PPF measured by the area integral of IK (Fig. 4c). To investigate whether temperature plays a role in KvF, we applied similar paired-pulse paradigms at 35°C with briefer AP waveform and inter-spike intervals (−90 to 100 mV, half-width: 0.15/0.3 ms, intervals: 0.5–5 ms) to mimic realistic temperature-dependent acceleration. Although it was evident that raising temperature speeded up activation and deactivation kinetics of these channels, we noted that PPF of IK remained pronounced (e.g. Kv1.1&1.2: PPF=256.2±28.0% at the interval of 1 ms; Supplementary Fig. 5). These results reinforce the notion that Kvs facilitate during repetitive activity regardless of their subtypes or experimental temperature.


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)

Mechanisms underlying Kv facilitation from recombinant Kv channels(a, b) IK (bottom panels) generated from CHO cells expressing Kv3.1 (blue, a) or Kv1.1&1.2 channels (magenta, b) by paired-pulse stimulation protocol (AP waveform: −90 to +100 mV, rise time: 0.3 ms, decay time: 0.6 ms, paired-pulse interval: 1 to 8 ms with increment of 0.5 ms, top panels). (c) PPF in the area integral of IK is summarized for CHO cells transfected with Kv3.1 (blue circles, n=8) or Kv1.1&1.2 (magenta circles, n=6) constructs. The solid lines are fits to a single exponential function and time constants are shown in the figure. (d–f) The first pair of IK in a are focused to show the time difference (Δt) between the peak of APs and that of corresponding IK (d). Note the dramatic early onset of the 2nd IK compared to the 1st IK. Quantitative analysis of Δt are demonstrated for expression of Kv3.1 (n=8, e) or Kv1.1&1.2 (n=6, f). (g–j) Voltage steps from −120 to 20 mV (10 ms long, top panels) applied to elicit IK from a CHO cell expressing Kv3.1 (middle panels) or Kv1.1&1.2 (bottom panels) with (h) or without (g) the pre-pulse (−120 to 100 mV, rise time: 0.3 ms, decay time: 0.6 ms). The amplitude of IK at varied potentials, measured at 2 ms after beginning of depolarization steps (dotted lines), is plotted in i (Kv3.1, n=4) and j (Kv1.1&1.2, n=4). Error bars indicate ± s.e.m.
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Figure 4: Mechanisms underlying Kv facilitation from recombinant Kv channels(a, b) IK (bottom panels) generated from CHO cells expressing Kv3.1 (blue, a) or Kv1.1&1.2 channels (magenta, b) by paired-pulse stimulation protocol (AP waveform: −90 to +100 mV, rise time: 0.3 ms, decay time: 0.6 ms, paired-pulse interval: 1 to 8 ms with increment of 0.5 ms, top panels). (c) PPF in the area integral of IK is summarized for CHO cells transfected with Kv3.1 (blue circles, n=8) or Kv1.1&1.2 (magenta circles, n=6) constructs. The solid lines are fits to a single exponential function and time constants are shown in the figure. (d–f) The first pair of IK in a are focused to show the time difference (Δt) between the peak of APs and that of corresponding IK (d). Note the dramatic early onset of the 2nd IK compared to the 1st IK. Quantitative analysis of Δt are demonstrated for expression of Kv3.1 (n=8, e) or Kv1.1&1.2 (n=6, f). (g–j) Voltage steps from −120 to 20 mV (10 ms long, top panels) applied to elicit IK from a CHO cell expressing Kv3.1 (middle panels) or Kv1.1&1.2 (bottom panels) with (h) or without (g) the pre-pulse (−120 to 100 mV, rise time: 0.3 ms, decay time: 0.6 ms). The amplitude of IK at varied potentials, measured at 2 ms after beginning of depolarization steps (dotted lines), is plotted in i (Kv3.1, n=4) and j (Kv1.1&1.2, n=4). Error bars indicate ± s.e.m.
Mentions: To explore the mechanisms underlying heterogeneity in KvF, we did paired-pulse experiments in CHO cell lines expressing recombinant homomeric Kv3.1 or heteromeric Kv1.1&1.2 channels, which constituted the major subunits of native Kvs 18, 19, 21–23 in the calyx of Held synapse. Simple spherical morphology of CHO cells also ensured accurate measurement of IK with minimal space-clamp errors. We found that the PPF in Kv1.1&1.2 currents was more robust (e.g. PPF for Kv1.1&1.2: 495.5±55.8% vs. for Kv3.1: 389.4±31.8% at the interval of 1 ms) and decayed much slower with increased inter-spike intervals than that in Kv3.1 currents (τ=1.0 ms for Kv1.1&1.2 vs. τ=0.4 ms for Kv3.1, Fig. 4a–c), in line with the observations from native IK-HT and IK-LT in the nerve terminal (Fig. 1). Most notably, the temporal onset of IK evoked by the 2nd spikes was shifted towards to the early phase of the pseudo-spikes, as quantified by the time difference between the peak of APs and that of their evoked IK (Fig. 4d). The timing shift of the 2nd IK declined exponentially over prolonged inter-spike intervals with the comparable time constants (Kv3.1: 0.4 ms vs. Kv1.1&1.2: 2.4 ms, Fig. 4e,f) to those of PPF measured by the area integral of IK (Fig. 4c). To investigate whether temperature plays a role in KvF, we applied similar paired-pulse paradigms at 35°C with briefer AP waveform and inter-spike intervals (−90 to 100 mV, half-width: 0.15/0.3 ms, intervals: 0.5–5 ms) to mimic realistic temperature-dependent acceleration. Although it was evident that raising temperature speeded up activation and deactivation kinetics of these channels, we noted that PPF of IK remained pronounced (e.g. Kv1.1&1.2: PPF=256.2±28.0% at the interval of 1 ms; Supplementary Fig. 5). These results reinforce the notion that Kvs facilitate during repetitive activity regardless of their subtypes or experimental temperature.

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