1. Neuroscience

NaV1.1 is essential for proprioceptive signaling and motor behaviors

  1. Cyrrus M Espino
  2. Cheyanne M Lewis
  3. Serena Ortiz
  4. Miloni S Dalal
  5. Snigdha Garlapalli
  6. Kaylee M Wells
  7. Darik A O'Neil
  8. Katherine A Wilkinson
  9. Theanne N Griffith  Is a corresponding author
  1. University of California, Davis, United States
  2. San Jose State University, United States
  3. Rutgers, The State University of New Jersey, United States
  4. Marine Biological Laboratory, United States
https://doi.org/10.7554/eLife.79917
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Cite this article
  1. Cyrrus M Espino
  2. Cheyanne M Lewis
  3. Serena Ortiz
  4. Miloni S Dalal
  5. Snigdha Garlapalli
  6. Kaylee M Wells
  7. Darik A O'Neil
  8. Katherine A Wilkinson
  9. Theanne N Griffith
(2022)
NaV1.1 is essential for proprioceptive signaling and motor behaviors
eLife 11:e79917.
https://doi.org/10.7554/eLife.79917
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Abstract

The voltage-gated sodium channel (NaV), NaV1.1, is well-studied in the central nervous system; conversely, its contribution to peripheral sensory neuron function is more enigmatic. Here, we identify a new role for NaV1.1 in mammalian proprioception. RNAscope analysis and in vitro patch clamp recordings in genetically identified mouse proprioceptors show ubiquitous channel expression and significant contributions to intrinsic excitability. Notably, genetic deletion of NaV1.1 in sensory neurons caused profound and visible motor coordination deficits in conditional knockout mice of both sexes, similar to conditional Piezo2-knockout animals, suggesting this channel is a major contributor to sensory proprioceptive transmission. Ex vivo muscle afferent recordings from conditional knockout mice found that loss of NaV1.1 leads to inconsistent and unreliable proprioceptor firing characterized by action potential failures during static muscle stretch; conversely, afferent responses to dynamic vibrations were unaffected. This suggests that while a combination of Piezo2 and other NaV isoforms are sufficient to elicit activity in response to transient stimuli, NaV1.1 is required for transmission of receptor potentials generated during sustained muscle stretch. Impressively, recordings from afferents of heterozygous conditional knockout animals were similarly impaired, and heterozygous conditional knockout mice also exhibited motor behavioral deficits. Thus, NaV1.1 haploinsufficiency in sensory neurons impairs both proprioceptor function and motor behaviors. Importantly, human patients harboring NaV1.1 loss-of-function mutations often present with motor delays and ataxia; therefore, our data suggest sensory neuron dysfunction contributes to the clinical manifestations of neurological disorders in which NaV1.1 function is compromised. Collectively, we present the first evidence that NaV1.1 is essential for mammalian proprioceptive signaling and behaviors.

Data availability

Source Data files have been uploaded to Mendeley for all figures (https://data.mendeley.com/datasets/kt23th75v9). Code has been uploaded to GitHub (https://github.com/doctheagrif/Current-Clamp-Matlab-Code_O-Neil-DA). A key resources table with specific organism and reagent information has been included in the methods section.

The following data sets were generated

Article and author information

Author details

  1. Cyrrus M Espino

    Department of Physiology and Membrane Biology, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2708-4577

  2. Cheyanne M Lewis

    Department of Physiology and Membrane Biology, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0057-2047

  3. Serena Ortiz

    Department of Biological Science, San Jose State University, San Jose, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Miloni S Dalal

    Department of Pharmacology, Physiology, and Neuroscience, Rutgers, The State University of New Jersey, Newark, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Snigdha Garlapalli

    Undergraduate program in Psychology, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Kaylee M Wells

    Neurobiology, Marine Biological Laboratory, Woods Hole, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Darik A O'Neil

    Neurobiology, Marine Biological Laboratory, Woods Hole, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Katherine A Wilkinson

    Department of Biological Science, San Jose State University, San Jose, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2692-5533

  9. Theanne N Griffith

    Department of Physiology and Membrane Biology, University of California, Davis, Davis, United States
    For correspondence
    tgriffith@ucdavis.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0090-6286

Funding

Burroughs Wellcome Fund

  • Theanne N Griffith

National Institute of General Medical Sciences (5T32GM099608-10)

  • Cyrrus M Espino

National Institute of General Medical Sciences (1T32GM1144303-01A1)

  • Cyrrus M Espino

National Institute of General Medical Sciences (5SC3GM127195)

  • Katherine A Wilkinson

National Institute of General Medical Sciences (5R25GM71381)

  • Serena Ortiz

National Institute of Neurological Disorders and Stroke (R25NS063307)

  • Kaylee M Wells
  • Darik A O'Neil

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

Ethics

Animal experimentation: Animal use was conducted according to guidelines from the National Institutes of Health's Guide for the Care and Use of Laboratory Animals and was approved by the Institutional Animal Care and Use Committee of Rutgers University-Newark (PROTO201900161), UC Davis (#21947 and #22438) and San José State University (#990, ex vivo muscle recordings).

Copyright

© 2022, Espino 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. Cyrrus M Espino
  2. Cheyanne M Lewis
  3. Serena Ortiz
  4. Miloni S Dalal
  5. Snigdha Garlapalli
  6. Kaylee M Wells
  7. Darik A O'Neil
  8. Katherine A Wilkinson
  9. Theanne N Griffith
(2022)
NaV1.1 is essential for proprioceptive signaling and motor behaviors
eLife 11:e79917.
https://doi.org/10.7554/eLife.79917

Share this article

https://doi.org/10.7554/eLife.79917

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