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 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 CO(2). 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 CO(2)/H(+)-dependent drive to breathe, are hyper-excitable in slices from Scn1a(ΔE26) mice. These results show loss of Scn1a function can disrupt respiratory control at the cellular and whole animal levels.