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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

Strong impact of Kv facilitation on synaptic input-output relationship(a, b) Representative recordings of presynaptic Ca2+ currents (Pre-ICa, bottom) from the calyces elicited by simulated AP trains (top) at 200 Hz (a) or 600 Hz (b) before (black traces) and after (red traces) attenuating K-LT facilitation. The amplitude of Pre-ICa is normalized to that of the first Pre-ICa during the train stimuli and plotted against stimulus time (the time for the 1st AP stimulation is set as zero). The solid lines in the right panels are fits to a single or double exponential function and the time constants are given (n=9 for 200 Hz and n=6 for 600 Hz group). (c) Simultaneous recordings of Pre-ICa (middle) and excitatory postsynaptic currents (Post-IEPSC, bottom) from the calyx of Held synapse repeatedly evoked by simulated spikes at 400 Hz (top) with normal (grey traces) or attenuated (pink traces) K-LT facilitation. Average traces of five repeats for each group are highlighted in black or red. Recording configuration is depicted on the right. (d) The amplitude of Pre-ICa (top) over 400 Hz train stimuli is fitted with a single/dual exponential function as shown with the solid lines. The Post-IEPSC (bottom) are described by a single (black line, with normal K-LT facilitation) or double (red line, with attenuated K-LT facilitation) exponential function (n=8 for each group). The amplitude of both Pre-ICa and Post-IEPSC are normalized to that of the first response in a train and plotted against stimulus time. Error bars indicate ± s.e.m.
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Figure 7: Strong impact of Kv facilitation on synaptic input-output relationship(a, b) Representative recordings of presynaptic Ca2+ currents (Pre-ICa, bottom) from the calyces elicited by simulated AP trains (top) at 200 Hz (a) or 600 Hz (b) before (black traces) and after (red traces) attenuating K-LT facilitation. The amplitude of Pre-ICa is normalized to that of the first Pre-ICa during the train stimuli and plotted against stimulus time (the time for the 1st AP stimulation is set as zero). The solid lines in the right panels are fits to a single or double exponential function and the time constants are given (n=9 for 200 Hz and n=6 for 600 Hz group). (c) Simultaneous recordings of Pre-ICa (middle) and excitatory postsynaptic currents (Post-IEPSC, bottom) from the calyx of Held synapse repeatedly evoked by simulated spikes at 400 Hz (top) with normal (grey traces) or attenuated (pink traces) K-LT facilitation. Average traces of five repeats for each group are highlighted in black or red. Recording configuration is depicted on the right. (d) The amplitude of Pre-ICa (top) over 400 Hz train stimuli is fitted with a single/dual exponential function as shown with the solid lines. The Post-IEPSC (bottom) are described by a single (black line, with normal K-LT facilitation) or double (red line, with attenuated K-LT facilitation) exponential function (n=8 for each group). The amplitude of both Pre-ICa and Post-IEPSC are normalized to that of the first response in a train and plotted against stimulus time. Error bars indicate ± s.e.m.

Mentions: Lacking ideal blockers, which only inhibit activity-dependent facilitation of Kvs without affecting their basal properties, precluded us from pharmacologically examining the physiological roles of KvF in high-frequency spiking. To overcome this difficulty, we performed computer simulations by creating a modified Hodgkin-Huxley (H-H) model cell (capacitance 6 pF and resting potential -80 mV) containing four components [i.e. potassium conductance (gK-HT and gK-LT), leak conductance (gL) and sodium conductance (gNa)] (Fig. 6a,b), where gK-HT, gK-LT, gL and gNa were free variables and APs were initiated by a brief inward square current (2 nA) 16, 28. The gating kinetics of gNa was established by fitting activation, deactivation and inactivation of INa obtained from the outside-out patches near the heminode region of calyceal terminals (Supplementary Fig. 6). Subsequently we incorporated this conductance along with two components of Kvs derived from the Markov model into the modified H-H model cell and produced AP trains which had the similar waveform to those realistic spikes recorded from the nerve terminal and as well as frequency-dependent adaptation (200–600 Hz, Fig. 6b, 7a–c). Figure 6b showed a simulated 400 Hz train, during which IK-LT but not IK-HT facilitated greatly, consistent with the experimental evidence of their distinct decay time courses for PPF (Fig. 1e,f). As revealed by our model (Fig. 5), fast deactivation kinetics of IK-HT might account for the lack of facilitation, particularly when evoked by a real AP train with use-dependent reduction in the amplitude. To specifically delineate the function of facilitation of IK-LT, we manually adjusted the deactivation rate constant β (Table 2: parameter c) until activity-dependent facilitation was largely removed while the amplitude of the 1st IK-LT was maintained by increasing its total conductance. Under these conditions, we disclosed that attenuation of IK-LT facilitation eliminated activity-dependent reduction in the spike amplitude and elevated the plateau potential in the AP train (Fig. 6b). Surprisingly, INa derived from the model cell with minimal IK-LT facilitation showed more prominent use-dependent inactivation, and yet remained sufficient to drive the spikes to higher amplitude. Activity-dependent decrease in the spike amplitude has classically been viewed as a result of Na+ channel inactivation 2, 7, 11, however the last line of our simulation results suggests that IK-LT facilitation can play an active role in regulating the AP amplitude by counteracting INa during repetitive activity.


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)

Strong impact of Kv facilitation on synaptic input-output relationship(a, b) Representative recordings of presynaptic Ca2+ currents (Pre-ICa, bottom) from the calyces elicited by simulated AP trains (top) at 200 Hz (a) or 600 Hz (b) before (black traces) and after (red traces) attenuating K-LT facilitation. The amplitude of Pre-ICa is normalized to that of the first Pre-ICa during the train stimuli and plotted against stimulus time (the time for the 1st AP stimulation is set as zero). The solid lines in the right panels are fits to a single or double exponential function and the time constants are given (n=9 for 200 Hz and n=6 for 600 Hz group). (c) Simultaneous recordings of Pre-ICa (middle) and excitatory postsynaptic currents (Post-IEPSC, bottom) from the calyx of Held synapse repeatedly evoked by simulated spikes at 400 Hz (top) with normal (grey traces) or attenuated (pink traces) K-LT facilitation. Average traces of five repeats for each group are highlighted in black or red. Recording configuration is depicted on the right. (d) The amplitude of Pre-ICa (top) over 400 Hz train stimuli is fitted with a single/dual exponential function as shown with the solid lines. The Post-IEPSC (bottom) are described by a single (black line, with normal K-LT facilitation) or double (red line, with attenuated K-LT facilitation) exponential function (n=8 for each group). The amplitude of both Pre-ICa and Post-IEPSC are normalized to that of the first response in a train and plotted against stimulus time. Error bars indicate ± s.e.m.
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Related In: Results  -  Collection

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Figure 7: Strong impact of Kv facilitation on synaptic input-output relationship(a, b) Representative recordings of presynaptic Ca2+ currents (Pre-ICa, bottom) from the calyces elicited by simulated AP trains (top) at 200 Hz (a) or 600 Hz (b) before (black traces) and after (red traces) attenuating K-LT facilitation. The amplitude of Pre-ICa is normalized to that of the first Pre-ICa during the train stimuli and plotted against stimulus time (the time for the 1st AP stimulation is set as zero). The solid lines in the right panels are fits to a single or double exponential function and the time constants are given (n=9 for 200 Hz and n=6 for 600 Hz group). (c) Simultaneous recordings of Pre-ICa (middle) and excitatory postsynaptic currents (Post-IEPSC, bottom) from the calyx of Held synapse repeatedly evoked by simulated spikes at 400 Hz (top) with normal (grey traces) or attenuated (pink traces) K-LT facilitation. Average traces of five repeats for each group are highlighted in black or red. Recording configuration is depicted on the right. (d) The amplitude of Pre-ICa (top) over 400 Hz train stimuli is fitted with a single/dual exponential function as shown with the solid lines. The Post-IEPSC (bottom) are described by a single (black line, with normal K-LT facilitation) or double (red line, with attenuated K-LT facilitation) exponential function (n=8 for each group). The amplitude of both Pre-ICa and Post-IEPSC are normalized to that of the first response in a train and plotted against stimulus time. Error bars indicate ± s.e.m.
Mentions: Lacking ideal blockers, which only inhibit activity-dependent facilitation of Kvs without affecting their basal properties, precluded us from pharmacologically examining the physiological roles of KvF in high-frequency spiking. To overcome this difficulty, we performed computer simulations by creating a modified Hodgkin-Huxley (H-H) model cell (capacitance 6 pF and resting potential -80 mV) containing four components [i.e. potassium conductance (gK-HT and gK-LT), leak conductance (gL) and sodium conductance (gNa)] (Fig. 6a,b), where gK-HT, gK-LT, gL and gNa were free variables and APs were initiated by a brief inward square current (2 nA) 16, 28. The gating kinetics of gNa was established by fitting activation, deactivation and inactivation of INa obtained from the outside-out patches near the heminode region of calyceal terminals (Supplementary Fig. 6). Subsequently we incorporated this conductance along with two components of Kvs derived from the Markov model into the modified H-H model cell and produced AP trains which had the similar waveform to those realistic spikes recorded from the nerve terminal and as well as frequency-dependent adaptation (200–600 Hz, Fig. 6b, 7a–c). Figure 6b showed a simulated 400 Hz train, during which IK-LT but not IK-HT facilitated greatly, consistent with the experimental evidence of their distinct decay time courses for PPF (Fig. 1e,f). As revealed by our model (Fig. 5), fast deactivation kinetics of IK-HT might account for the lack of facilitation, particularly when evoked by a real AP train with use-dependent reduction in the amplitude. To specifically delineate the function of facilitation of IK-LT, we manually adjusted the deactivation rate constant β (Table 2: parameter c) until activity-dependent facilitation was largely removed while the amplitude of the 1st IK-LT was maintained by increasing its total conductance. Under these conditions, we disclosed that attenuation of IK-LT facilitation eliminated activity-dependent reduction in the spike amplitude and elevated the plateau potential in the AP train (Fig. 6b). Surprisingly, INa derived from the model cell with minimal IK-LT facilitation showed more prominent use-dependent inactivation, and yet remained sufficient to drive the spikes to higher amplitude. Activity-dependent decrease in the spike amplitude has classically been viewed as a result of Na+ channel inactivation 2, 7, 11, however the last line of our simulation results suggests that IK-LT facilitation can play an active role in regulating the AP amplitude by counteracting INa during repetitive activity.

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