Disordered breathing in a mouse model of Dravet syndrome

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 <i>Scn1a</i> missense mutation (A1783V) conditionally in inhibitory neurons (<i>Slc32a1</i>^cre/+<i>::Scn1a^{A1783V fl/+}</i>; defined as <i>Scn1a^ΔE26</i>) 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 <i>Scn1a</i> 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 <i>Scn1a^ΔE26</i> mice. These results show loss of <i>Scn1a</i> function can disrupt respiratory control at the cellular and whole animal levels.