Relation between serotoninergic brainstem dysfunction and epilepsy-related respiratory dysfunction in Dravet syndrome – seroDRAVET

Dravet Syndrome (DS) is a severe epileptic encephalopathy, which main cause is mutations of SCN1A and which associated with high risk of sudden death (SUDEP). Experimental and clinical data suggest that most SUDEP cases result from postictal brainstem dysfunction, including central respiratory arrest. fatal post-ictal apnea could be facilitated by chronic alterations of respiratory functions. There is a body of evidence suggesting involvement of serotonin (5HT) dysfunction in the pathogenesis of epilepsy in DS. On the other hand, 5HT also plays a key role in the regulation of respiration and it has repeatedly been suggested that 5HT dysfunction might increase the risk of seizure-related respiratory dysfunction and, eventually, the risk of SUDEP. SUDEP in DS might therefore be the result of a seizure-induced fatal apnea in a patient who has developed epilepsy-related vulnerability to central respiratory dysfunction favored by 5HT dysfunction. However, several issues remain unclear, including the temporal dynamic of the onset and evolution of the respiratory vulnerability in DS, the relation between the alterations of the 5HT pathway observed in DS and epilepsy-related respiratory dysfunction and whether or not modulation of 5HT neuronal activity does reduce the risk of epilepsy-related respiratory dysfunction
The seroDRAVET project will use an integrative approach with the objective of (i) better understanding the molecular mechanisms that underlie epilepsy-related vulnerability to central respiratory dysfunction and SUDEP in DS and (ii) developing hypotheses-driven approach to prevent seizure-related respiratory dysfunction. We will thus: (i) analyze the temporal relationship between evolution of epilepsy and alteration of respiratory function in a mouse model of DS; (ii) determine, both in rodents and in patients, the relation between respiratory dysfunction and alterations of the brainstem 5HT pathway investigated with PET/MRI; and (iii) validate using pharmacological and chemogenetic approaches that modulation of activity of 5HT neurons modifies the risk of seizure-related fatal apnea in DS.