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 (Slc32a1cre/+::Scn1aA1783V fl/+; defined as Scn1aΔE26) 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 Scn1aΔE26 mice. These results show loss of Scn1a function can disrupt respiratory control at the cellular and whole animal levels.
Highlights
Dravet syndrome (DS) is a severe form of early-onset epilepsy that is resistant to anti-epileptic drugs and has a high incidence of sudden unexpected death in epilepsy (SUDEP) (Kalume, 2013; Kearney, 2013; Shmuely et al, 2016)
Together with our sequencing data (Figure 1Aiii), these results suggest that the A1783V pathogenic variant is expressed by brainstem inhibitory neurons but possibly at slightly reduced levels compared to control
This mouse model presents with a respiratory phenotype reminiscent of that exhibited by DS patients (Figure 3)
Summary
Dravet syndrome (DS) (aka. severe myoclonic epilepsy of infancy) is a severe form of early-onset epilepsy that is resistant to anti-epileptic drugs and has a high incidence of sudden unexpected death in epilepsy (SUDEP) (Kalume, 2013; Kearney, 2013; Shmuely et al, 2016). Patients with DS exhibited a blunted ventilatory response to CO2 (Kim et al, 2018) This finding suggests that respiratory dysfunction, possibly at the level of respiratory chemoreceptors (neurons that regulate breathing in response to changes in tissue CO2/H+), contributes to the pathology of DS. Leading hypotheses propose that seizure activity disrupts respiratory control by a feed-forward mechanisms involving spreading depolarization (Aiba and Noebels, 2015) or activation of inhibitory subcortical projections to brainstem respiratory centers (Dlouhy et al, 2015; Lacuey et al, 2017) Consistent with the latter possibility, there is evidence that activity of serotonergic neurons in the dorsal and medullary raphe regions in rats are suppressed during ictal and post-ictal periods (Zhan et al, 2016).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
