Roles of glycinergic neurons in Dravet syndrome-associated disordered breathing and mortality

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Summary Dravet syndrome (DS) is a severe form of epilepsy with a high rate of SUPEP. Respiratory failure is a leading cause of SUDEP, and DS patients' frequently exhibit disordered breathing. However, mechanisms underlying respiratory dysfunction in DS are unknown. Evidence suggests cortical seizures activate inhibitory projections to suppress brainstem function and result in death; however, a yet unexplored possibility is that DS-associated mutations directly affect brainstem respiratory centers and serve as a common substrate for both seizure and respiratory dysfunction. We recently showed that Scn1a transcript is highly expressed in brainstem inhibitory neurons, and expression of a DS-associated Scn1a mutation (A1783V) in inhibitory neurons resulted in cell autonomous loss of neural activity and disruption of respiratory function at the cellular and whole-animal levels. Therefore, I hypothesize that loss of Scn1a function directly impacts brainstem respiratory control. To test this, I will disrupt Scn1a function globally (Scn1a-/+), specifically in all VGAT+ inhibitory neurons and only in glycinergic neurons (GlyT2:A1783V) and determine whether these animals exhibit disordered breathing, seizures or premature death (Aim 1), and altered cellular activity of respiratory neurons (Aim 2). This work will provide novel insight into roles of glycinergic neurons in DS, and determine the extent to which loss of Scn1a function directly affect brainstem function.