1. Neuroscience

Disordered breathing in a mouse model of Dravet syndrome

  1. Fu-Shan Kuo
  2. Colin M Cleary
  3. Joseph L LoTurco
  4. Xinnian Chen
  5. Daniel K Mulkey  Is a corresponding author
  1. University of Connecticut, United States
https://doi.org/10.7554/eLife.43387
Share this article
Cite this article
  1. Fu-Shan Kuo
  2. Colin M Cleary
  3. Joseph L LoTurco
  4. Xinnian Chen
  5. Daniel K Mulkey
(2019)
Disordered breathing in a mouse model of Dravet syndrome
eLife 8:e43387.
https://doi.org/10.7554/eLife.43387
  2. Download BibTeX
  3. Download .RIS

Abstract

Dravet syndrome (DS) is a form of epilepsy with a high incidence of sudden unexpected death in epilepsy (SUDEP). Respiratory failure is a leading cause of SUDEP, and DS patients' frequently exhibit disordered breathing. Despite this, mechanisms underlying respiratory dysfunction in DS are unknown. We found that mice expressing a DS-associated Scn1a missense mutation (A1783V) conditionally in inhibitory neurons (Slc32a1cre/+::Scn1aA1783V fl/+; defined as Scn1aΔE26) exhibit spontaneous seizures, die prematurely and present a respiratory phenotype including hypoventilation, apnea, and a diminished ventilatory response to CO2. At the cellular level in the retrotrapezoid nucleus (RTN), we found inhibitory neurons expressing the Scn1a A1783V variant are less excitable, whereas glutamatergic chemosensitive RTN neurons, which are a key source of the CO2/H+-dependent drive to breathe, are hyper-excitable in slices from Scn1aΔE26 mice. These results show loss of Scn1a function can disrupt respiratory control at the cellular and whole animal levels.

Data availability

We have included source data files for all summary figures that do not include individual data points.

Article and author information

Author details

  1. Fu-Shan Kuo

    Department of Physiology and Neurobiology, University of Connecticut, Storrs, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Colin M Cleary

    Department of Physiology and Neurobiology, University of Connecticut, Storrs, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Joseph L LoTurco

    Department of Physiology and Neurobiology, University of Connecticut, Storrs, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Xinnian Chen

    Department of Physiology and Neurobiology, University of Connecticut, Storrs, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Daniel K Mulkey

    Department of Physiology and Neurobiology, University of Connecticut, Storrs, United States
    For correspondence
    daniel.mulkey@uconn.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7040-3927

Funding

National Institutes of Health (HL104101)

  • Daniel K Mulkey

Dravet Syndrome Foundation (AG180243)

  • Daniel K Mulkey

American Epilepsy Society

  • Fu-Shan Kuo

National Institutes of Health (NS104999)

  • Joseph L LoTurco

National Institutes of Health (HL142227)

  • Colin M Cleary

National Institutes of Health (HL137094)

  • Daniel K Mulkey

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

Reviewing Editor

  1. Jan-Marino Ramirez, Seattle Children's Research Institute and University of Washington, United States

Ethics

Animal experimentation: All animal use was in accordance with guidelines approved by the University of Connecticut Institutional Animal Care and Use Committee. (Protocols A16-034 and A17-002).

Version history

  1. Received: November 5, 2018
  2. Accepted: April 25, 2019
  3. Accepted Manuscript published: April 26, 2019 (version 1)
  4. Version of Record published: May 8, 2019 (version 2)

Copyright

© 2019, Kuo 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.

Metrics

  • 3,144
    views
  • 436
    downloads
  • 46
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Fu-Shan Kuo
  2. Colin M Cleary
  3. Joseph L LoTurco
  4. Xinnian Chen
  5. Daniel K Mulkey
(2019)
Disordered breathing in a mouse model of Dravet syndrome
eLife 8:e43387.
https://doi.org/10.7554/eLife.43387

Share this article

https://doi.org/10.7554/eLife.43387

Categories and tags

Research organism

Further reading

    1. Neuroscience

    Somatostatin-expressing parafacial neurons are CO2/H+ sensitive and regulate baseline breathing

    Colin M Cleary, Brenda M Milla ... Daniel K Mulkey
    Research Advance Updated

    Glutamatergic neurons in the retrotrapezoid nucleus (RTN) function as respiratory chemoreceptors by regulating breathing in response to tissue CO2/H+. The RTN and greater parafacial region may also function as a chemosensing network composed of CO2/H+-sensitive excitatory and inhibitory synaptic interactions. In the context of disease, we showed that loss of inhibitory neural activity in a mouse model of Dravet syndrome disinhibited RTN chemoreceptors and destabilized breathing (Kuo et al., 2019). Despite this, contributions of parafacial inhibitory neurons to control of breathing are unknown, and synaptic properties of RTN neurons have not been characterized. Here, we show the parafacial region contains a limited diversity of inhibitory neurons including somatostatin (Sst)-, parvalbumin (Pvalb)-, and cholecystokinin (Cck)-expressing neurons. Of these, Sst-expressing interneurons appear uniquely inhibited by CO2/H+. We also show RTN chemoreceptors receive inhibitory input that is withdrawn in a CO2/H+-dependent manner, and chemogenetic suppression of Sst+ parafacial neurons, but not Pvalb+ or Cck+ neurons, increases baseline breathing. These results suggest Sst-expressing parafacial neurons contribute to RTN chemoreception and respiratory activity.

    1. Developmental Biology
    2. Neuroscience

    A unique multi-synaptic mechanism involving acetylcholine and GABA regulates dopamine release in the nucleus accumbens through early adolescence in male rats

    Melody C Iacino, Taylor A Stowe ... Mark J Ferris
    Research Article Updated

    Adolescence is characterized by changes in reward-related behaviors, social behaviors, and decision-making. These behavioral changes are necessary for the transition into adulthood, but they also increase vulnerability to the development of a range of psychiatric disorders. Major reorganization of the dopamine system during adolescence is thought to underlie, in part, the associated behavioral changes and increased vulnerability. Here, we utilized fast scan cyclic voltammetry and microdialysis to examine differences in dopamine release as well as mechanisms that underlie differential dopamine signaling in the nucleus accumbens (NAc) core of adolescent (P28-35) and adult (P70-90) male rats. We show baseline differences between adult and adolescent-stimulated dopamine release in male rats, as well as opposite effects of the α6 nicotinic acetylcholine receptor (nAChR) on modulating dopamine release. The α6-selective blocker, α-conotoxin, increased dopamine release in early adolescent rats, but decreased dopamine release in rats beginning in middle adolescence and extending through adulthood. Strikingly, blockade of GABAA and GABAB receptors revealed that this α6-mediated increase in adolescent dopamine release requires NAc GABA signaling to occur. We confirm the role of α6 nAChRs and GABA in mediating this effect in vivo using microdialysis. Results herein suggest a multisynaptic mechanism potentially unique to the period of development that includes early adolescence, involving acetylcholine acting at α6-containing nAChRs to drive inhibitory GABA tone on dopamine release.

    1. Neuroscience

    The scheduling of adolescence with Netrin-1 and UNC5C

    Daniel Hoops, Robert Kyne ... Cecilia Flores
    Short Report

    Dopamine axons are the only axons known to grow during adolescence. Here, using rodent models, we examined how two proteins, Netrin-1 and its receptor, UNC5C, guide dopamine axons toward the prefrontal cortex and shape behaviour. We demonstrate in mice (Mus musculus) that dopamine axons reach the cortex through a transient gradient of Netrin-1-expressing cells – disrupting this gradient reroutes axons away from their target. Using a seasonal model (Siberian hamsters; Phodopus sungorus) we find that mesocortical dopamine development can be regulated by a natural environmental cue (daylength) in a sexually dimorphic manner – delayed in males, but advanced in females. The timings of dopamine axon growth and UNC5C expression are always phase-locked. Adolescence is an ill-defined, transitional period; we pinpoint neurodevelopmental markers underlying this period.