Disordered breathing in a mouse model of Dravet syndrome

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 entirely unknown. We found that mice expressing a recurrent SCN1a missense mutation (A1783V) conditionally in inhibitory neurons (SCN1aA1783V/+; mixed C57B/6 background) exhibit spontaneous seizures, die prematurely and present a respiratory phenotype similar to DS patients 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 chemosensitive RTN neurons, which are a key source of the CO2/H+-dependent drive to breathe, are hyper-excitable in slices from SCN1aA1783V/+ mice. These results show loss of SCN1a function can disrupt brainstem respiratory control including at the level of the RTN.