Disordered breathing in a mouse model of Dravet syndrome

• Published in: eLife Vol. 8
• Main Authors: Kuo, Fu-Shan, Cleary, Colin M, LoTurco, Joseph J, Chen, Xinnian, Mulkey, Daniel K
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 26.04.2019; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Action Potentials - genetics; Animals; Apnea; Body temperature; brainstem; Carbon dioxide; Carbon Dioxide - toxicity; chemoreception; Convulsions & seizures; Death; Disease Models, Animal; Epilepsies, Myoclonic - genetics; Epilepsies, Myoclonic - physiopathology; Epilepsy; Experiments; Glutamatergic transmission; Health aspects; Humans; Hypoventilation; Mice; Missense mutation; Mutation; Mutation, Missense - genetics; NAV1.1 Voltage-Gated Sodium Channel - genetics; Neurons; Neurons - metabolism; Neurons - pathology; Neuroscience; Neurosciences; Phenotypes; Physiological aspects; Respiration; Respiration - genetics; Respiratory failure; Respiratory insufficiency; Retrotrapezoid nucleus; SCN1a missense mutation; Seizures; Seizures (Medicine); Seizures - genetics; Seizures - physiopathology; Sodium channels (voltage-gated); Statistical analysis; Sudden Unexpected Death in Epilepsy - pathology; SUDEP; United States; United States > US; SCN1a missense mutation; mouse; SUDEP; neuroscience; brainstem; chemoreception; retrotrapezoid nucleus
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.43387

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 missense mutation (A1783V) conditionally in inhibitory neurons ( ; defined as ) exhibit spontaneous seizures, die prematurely and present a respiratory phenotype including hypoventilation, apnea, and a diminished ventilatory response to CO . At the cellular level in the retrotrapezoid nucleus (RTN), we found inhibitory neurons expressing the A1783V variant are less excitable, whereas glutamatergic chemosensitive RTN neurons, which are a key source of the CO /H -dependent drive to breathe, are hyper-excitable in slices from mice. These results show loss of function can disrupt respiratory control at the cellular and whole animal levels.