Exploring the function of the central control of breathing in mice with sodium-channel mutations causing epilepsy, implication for the sudden unexpected death in epilepsy (SUDEP).

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Breathing is essential for life and a dysfunction of the neuronal network that controls this behaviour is suspected to be involved in several neurological diseases. The PreBötzinger Complex (PreBötC) is the central generator of the inspiratory breathing activity located in the brainstem. This research proposal is designed to unravel the consequences, of known epilepsy-causing mutations in genes encoding voltage gated sodium-channels, on the function of the PreBötC. The project aims to investigate the breathing activity in vivo and in vitro in mice with targeted knock-out and knock-in mutations in these genes and their possible consequences for SUDEP. Sudden unexpected death in epilepsy (SUDEP) is the most common direct cause of death in people suffering from epilepsy. Specifically, mice with mutations in the genes SCN1A and SCN2A will be examined. First, breathing will be characterized in great detail in the mutant mice and compared to the wildtype (WT) littermates. I propose to use in vivo whole body plethysmography recordings of freely moving mice to characterize the breathing parameters (objective1). Second, I will utilize in vitro electrophysiology and histology, obtained from brainstem slices containing the PreBötC, to dissect the possible pathological mechanisms at the network and cellular level caused by these mutations (objective 2). In my previous work, I have already shown how monogenic mutations (CACNA1A and NDUFS4, preliminary work) can lead to severe and potential lethal dysfunction of the central control of breathing. The results of objective 1 and 2 will provide, not only, an understanding how mutations in these genes might cause the pathology, but will enhance our knowledge of the fundamental function of the central control of breathing. Furthermore, in a third set of experiments, I propose to investigate the effects of Antiepileptic drugs (AED) on the function of the PreBötC in vitro and in vivo (objective 3) in wildtype and mutant mice to understand how these drugs might affect the function of the PreBötC. The exact pathophysiology leading to SUDEP is not well understood. A dysfunction of the autonomic control of heart beat and breathing are suspected to be involved in SUDEP. The function of the PreBötC might therefore play a crucial role in the fatal cascade leading to the death in these patients. The results of the first, second and third series of experiments will be correlated and combined to unravel if and how a dysregulation of the PreBötC could be involved in these events.