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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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Activity-dependent facilitation of IK is Ca2+-independent(a) Whole-cell recordings of IK evoked by a typical presynaptic AP trains (previously obtained from the calyx of Held nerve terminal, the 1st AP has an amplitude of 110 mV, half-width of 0.28 ms and depolarizing after potential (DAP) of 9.6 mV) at 400 Hz with a duration of 200 ms (only the first 10 APs are shown) in the absence or presence of Ca2+ buffer EGTA at low concentration (0.5 mM) or BAPTA at high concentration (30 mM). (b–d) The normalized amplitude of IK (to the first response in a train) is summarized for no-Ca2+ buffer (n=4, b), EGTA (n=6, c) and BAPTA (n=5, d) groups. Error bars indicate ± s.e.m.
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Figure 3: Activity-dependent facilitation of IK is Ca2+-independent(a) Whole-cell recordings of IK evoked by a typical presynaptic AP trains (previously obtained from the calyx of Held nerve terminal, the 1st AP has an amplitude of 110 mV, half-width of 0.28 ms and depolarizing after potential (DAP) of 9.6 mV) at 400 Hz with a duration of 200 ms (only the first 10 APs are shown) in the absence or presence of Ca2+ buffer EGTA at low concentration (0.5 mM) or BAPTA at high concentration (30 mM). (b–d) The normalized amplitude of IK (to the first response in a train) is summarized for no-Ca2+ buffer (n=4, b), EGTA (n=6, c) and BAPTA (n=5, d) groups. Error bars indicate ± s.e.m.

Mentions: To examine whether KvF occurs during physiological activity, we recorded IK from the mature calyceal terminals using previously obtained native AP trains at various frequencies (200–400 Hz) as voltage-clamp templates (Fig. 3 and Supplementary Fig. 3). Typically theses spikes displayed a slight use-dependent reduction in amplitude and persistent plateau potential resulting from depolarizing after-potential (DAP) driven by resurgent Na+ currents (INa) 24. Figure 3a showed an example of presynaptic IK (with P/4 digital subtraction of leak and capacitive currents) evoked by 400 Hz AP trains, where the IK amplitude increased significantly in the first 5–10 spikes and sustained throughout the entire train at a level of 20–30% above the first response (1st IK: 1.35±0.21 nA, 10th IK: 1.65±0.25 nA, Fig. 3c). Such facilitation was readily reversed upon cessation of stimulation, and the magnitude of facilitation depended on the AP frequency and DAP (Supplementary Fig. 3). The profile of IK facilitation was very similar to that estimated by pharmacologically isolated (i.e. TEA and DTX sensitive) currents without P/N subtraction, indicating that this feature of Kvs cannot be attributed to the voltage-clamp errors (Supplementary Fig. 4). Similar characteristics of IK were observed from hippocampal DGIs, cerebellar SNs and PCs at 22°C or 35°C (Supplementary Fig. 1d–f). A prominent example was SNs where realistic AP trains at 400 Hz generated more than 300% facilitation of IK at physiological temperature either from the whole cells or outside-out patches. In contrast, IK evoked by native APs at 50 Hz in slow-spiking CA1 neurons dramatically decreased, likely as a result of use-dependent inactivation of the Kvs (Supplementary Fig. 2). These results demonstrate that KvF during natural bursts of activity is frequency-dependent, being most noticeable in fast neurons at high-frequency firing but largely absent in slow-spiking neurons.


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)

Activity-dependent facilitation of IK is Ca2+-independent(a) Whole-cell recordings of IK evoked by a typical presynaptic AP trains (previously obtained from the calyx of Held nerve terminal, the 1st AP has an amplitude of 110 mV, half-width of 0.28 ms and depolarizing after potential (DAP) of 9.6 mV) at 400 Hz with a duration of 200 ms (only the first 10 APs are shown) in the absence or presence of Ca2+ buffer EGTA at low concentration (0.5 mM) or BAPTA at high concentration (30 mM). (b–d) The normalized amplitude of IK (to the first response in a train) is summarized for no-Ca2+ buffer (n=4, b), EGTA (n=6, c) and BAPTA (n=5, d) groups. Error bars indicate ± s.e.m.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4503407&req=5

Figure 3: Activity-dependent facilitation of IK is Ca2+-independent(a) Whole-cell recordings of IK evoked by a typical presynaptic AP trains (previously obtained from the calyx of Held nerve terminal, the 1st AP has an amplitude of 110 mV, half-width of 0.28 ms and depolarizing after potential (DAP) of 9.6 mV) at 400 Hz with a duration of 200 ms (only the first 10 APs are shown) in the absence or presence of Ca2+ buffer EGTA at low concentration (0.5 mM) or BAPTA at high concentration (30 mM). (b–d) The normalized amplitude of IK (to the first response in a train) is summarized for no-Ca2+ buffer (n=4, b), EGTA (n=6, c) and BAPTA (n=5, d) groups. Error bars indicate ± s.e.m.
Mentions: To examine whether KvF occurs during physiological activity, we recorded IK from the mature calyceal terminals using previously obtained native AP trains at various frequencies (200–400 Hz) as voltage-clamp templates (Fig. 3 and Supplementary Fig. 3). Typically theses spikes displayed a slight use-dependent reduction in amplitude and persistent plateau potential resulting from depolarizing after-potential (DAP) driven by resurgent Na+ currents (INa) 24. Figure 3a showed an example of presynaptic IK (with P/4 digital subtraction of leak and capacitive currents) evoked by 400 Hz AP trains, where the IK amplitude increased significantly in the first 5–10 spikes and sustained throughout the entire train at a level of 20–30% above the first response (1st IK: 1.35±0.21 nA, 10th IK: 1.65±0.25 nA, Fig. 3c). Such facilitation was readily reversed upon cessation of stimulation, and the magnitude of facilitation depended on the AP frequency and DAP (Supplementary Fig. 3). The profile of IK facilitation was very similar to that estimated by pharmacologically isolated (i.e. TEA and DTX sensitive) currents without P/N subtraction, indicating that this feature of Kvs cannot be attributed to the voltage-clamp errors (Supplementary Fig. 4). Similar characteristics of IK were observed from hippocampal DGIs, cerebellar SNs and PCs at 22°C or 35°C (Supplementary Fig. 1d–f). A prominent example was SNs where realistic AP trains at 400 Hz generated more than 300% facilitation of IK at physiological temperature either from the whole cells or outside-out patches. In contrast, IK evoked by native APs at 50 Hz in slow-spiking CA1 neurons dramatically decreased, likely as a result of use-dependent inactivation of the Kvs (Supplementary Fig. 2). These results demonstrate that KvF during natural bursts of activity is frequency-dependent, being most noticeable in fast neurons at high-frequency firing but largely absent in slow-spiking neurons.

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