1. Neuroscience

Kv3.3 subunits control presynaptic action potential waveform and neurotransmitter release at a central excitatory synapse

  1. Amy Richardson
  2. Victoria Ciampani
  3. Mihai Stancu
  4. Kseniia Bondarenko
  5. Sherylanne Newton
  6. Joern R Steinert
  7. Nadia Conny Pilati
  8. Bruce P Graham
  9. Conny Kopp-Scheinpflug
  10. Ian Forsythe  Is a corresponding author
  1. University of Leicester, United Kingdom
  2. Ludwig-Maximilians-Universität München, Germany
  3. Istituto di Ricerca Pediatrica Citta'della Speranza, Italy
  4. University of Stirling, United Kingdom
https://doi.org/10.7554/eLife.75219
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  1. Amy Richardson
  2. Victoria Ciampani
  3. Mihai Stancu
  4. Kseniia Bondarenko
  5. Sherylanne Newton
  6. Joern R Steinert
  7. Nadia Conny Pilati
  8. Bruce P Graham
  9. Conny Kopp-Scheinpflug
  10. Ian Forsythe
(2022)
Kv3.3 subunits control presynaptic action potential waveform and neurotransmitter release at a central excitatory synapse
eLife 11:e75219.
https://doi.org/10.7554/eLife.75219
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Abstract

Kv3 potassium currents mediate rapid repolarization of action potentials (APs), supporting fast spikes and high repetition rates. Of the four Kv3 gene family members, Kv3.1 and Kv3.3 are highly expressed in the auditory brainstem and we exploited this to test for subunit-specific roles at the calyx of Held presynaptic terminal in the mouse. Deletion of Kv3.3 (but not Kv3.1) reduced presynaptic Kv3 channel immunolabelling, increased presynaptic AP duration and facilitated excitatory transmitter release; which in turn enhanced short-term depression during high frequency transmission. The response to sound was delayed in the Kv3.3KO, with higher spontaneous and lower evoked firing, thereby reducing signal-to-noise ratio. Computational modelling showed that the enhanced EPSC and short-term depression in the Kv3.3KO reflected increased vesicle release probability and accelerated activity-dependent vesicle replenishment. We conclude that Kv3.3 mediates fast repolarization for short precise APs, conserving transmission during sustained high-frequency activity at this glutamatergic excitatory synapse.

Data availability

Data generated in this study are included in the manuscript and supporting files. Source data files for each figure has been uploaded onto FigShare. Datasets Generated for the Ms "Kv3.3 subunits control presynaptic action potential waveform and neurotransmitter release at a central excitatory synapse" Authors: Ian D. Forsythe, Amy Richardson, Victoria Ciampani, Mihai Stancu, Kseniia Bondarenko, Sherylanne Newton, Joern Steinert, Nadia Pilati, Bruce Graham, Conny Kopp-Scheinpflug, 2022,https://figshare.com/s/9c0a07ed2fe5761cc281. The model code and associated data files are available at: Bruce Graham, 2021, https://github.com/bpgraham/CoH-Models

The following data sets were generated

Article and author information

Author details

  1. Amy Richardson

    epartment of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1552-2915

  2. Victoria Ciampani

    epartment of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, United Kingdom
    Competing interests
    No competing interests declared.

  3. Mihai Stancu

    Division of Neurobiology, Ludwig-Maximilians-Universität München, Munchen, Germany
    Competing interests
    No competing interests declared.

  4. Kseniia Bondarenko

    epartment of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, United Kingdom
    Competing interests
    No competing interests declared.

  5. Sherylanne Newton

    epartment of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8210-3526

  6. Joern R Steinert

    epartment of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, United Kingdom
    Competing interests
    No competing interests declared.

  7. Nadia Conny Pilati

    Istituto di Ricerca Pediatrica Citta'della Speranza, Padova, Italy
    Competing interests
    Nadia Conny Pilati, This author is employed by Autifony Therapeutics Ltd..

  8. Bruce P Graham

    Computing Science and Mathematics, University of Stirling, Stirling, United Kingdom
    Competing interests
    No competing interests declared.

  9. Conny Kopp-Scheinpflug

    Division of Neurobiology, Ludwig-Maximilians-Universität München, Munchen, Germany
    Competing interests
    No competing interests declared.

  10. Ian Forsythe

    epartment of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, United Kingdom
    For correspondence
    idf@le.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8216-0419

Funding

Biotechnology and Biological Sciences Research Council (R001154/1)

  • Ian Forsythe

Biotechnology and Biological Sciences Research Council (Case Award M016501)

  • Ian Forsythe

H2020 Health (ITN LISTEN 722098)

  • Ian Forsythe

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Henrique von Gersdorff, Oregon Health and Science University, United States

Ethics

Animal experimentation: Experiments were conducted in accordance with the Animals (Scientific Procedures) Act UK 1986 and as revised by the European Directive 2010/63/EU on the protection of animals used for scientific purposes. All procedures were approved by national oversight bodies (UK Home Office, or Bavarian district government, ROB-55.2-2532.Vet_02-18-1183) and the local animal research ethics review committees. In vivo experiments were conducted under anaesthesia: with a subcutaneous injection of 0.01ml/g MMF (0.5mg/kg body weight Medetomidine, 5.0mg/kg body weight Midazolam and 0.05mg/kg body weight Fentanyl). Every effort was made to minimise suffering and at the end of each procedure the animal was humanely killed using an approved method.

Version history

  1. Received: November 2, 2021
  2. Preprint posted: November 3, 2021 (view preprint)
  3. Accepted: April 29, 2022
  4. Accepted Manuscript published: May 5, 2022 (version 1)
  5. Accepted Manuscript updated: May 6, 2022 (version 2)
  6. Version of Record published: May 16, 2022 (version 3)

Copyright

© 2022, Richardson et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Amy Richardson
  2. Victoria Ciampani
  3. Mihai Stancu
  4. Kseniia Bondarenko
  5. Sherylanne Newton
  6. Joern R Steinert
  7. Nadia Conny Pilati
  8. Bruce P Graham
  9. Conny Kopp-Scheinpflug
  10. Ian Forsythe
(2022)
Kv3.3 subunits control presynaptic action potential waveform and neurotransmitter release at a central excitatory synapse
eLife 11:e75219.
https://doi.org/10.7554/eLife.75219

Share this article

https://doi.org/10.7554/eLife.75219

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