Disordered breathing in a mouse model of Dravet syndrome

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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 (Slc32a1^cre/+::Scn1a^{A1783V fl/+}; defined as Scn1a^ΔE26) 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 Scn1a^ΔE26mice. These results show loss of Scn1a function can disrupt respiratory control at the cellular and whole animal levels.

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

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Fu-Shan Kuo

Department of Physiology and Neurobiology, University of Connecticut, Storrs, United States

Competing interests
The authors declare that no competing interests exist.
Colin M Cleary

Department of Physiology and Neurobiology, University of Connecticut, Storrs, United States

Competing interests
The authors declare that no competing interests exist.
Joseph L LoTurco

Department of Physiology and Neurobiology, University of Connecticut, Storrs, United States

Competing interests
The authors declare that no competing interests exist.
Xinnian Chen

Department of Physiology and Neurobiology, University of Connecticut, Storrs, United States

Competing interests
The authors declare that no competing interests exist.
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.

"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.

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).

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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.