Prevention of SUDEP by milk whey: Role of CO2 chemoreception and serotonin

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Abstract Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with refractory epilepsy. Emerging data indicate that a substantial percentage of SUDEP is due to seizure-induced respiratory arrest. There is a gap in knowledge about how seizures cause apnea, who is at highest risk and what can be done to prevent it. We have found that postictal death is due to seizure-induced apnea in two genetic mouse models of human SUDEP (Scn1aR1407X and Scn8aN1768D mice). Our data indicate that seizures activate projections from the amygdala to the brainstem causing central apnea, and transient defects in CO2 homeostasis and serotonin (5-HT) neuron function. This is supported by data showing that 5-HT neurons, which are central CO2/pH chemoreceptors that stimulate breathing, are inhibited during seizures. The central hypothesis of the current proposal is that seizures impair CO2 chemoreception, in part by inhibiting 5-HT neurons, which increases the risk of a seizure becoming fatal. We have also found that a diet supplemented with milk whey causes a large reduction in the risk of SUDEP, and this may be due to an increase in 5-HT. This proposal will use Scn1aR1407X and Scn8aN1768D mice to carry out the following specific aims. 1) Determine the role of impaired CO2 chemoreception in fatal post-ictal apnea. Working hypothesis: Seizures inhibit CO2 chemoreception, which increases the risk of fatal apnea. Our preliminary data indicate that generalized seizures cause a large post-ictal decrease in ventilation, a decrease in the hypercapnic ventilatory response (HCVR), and a transient drop in body temperature. All three of these homeostatic brainstem functions are controlled by serotonin neurons. We will use 24-hour monitoring of EEG, EMG, EKG, plethysmography, body temperature and video in a mouse epilepsy monitoring unit (EMU) to study changes due to spontaneous seizures. 2) We will define the contribution of 5-HT system dysfunction to postictal hypoventilation and apnea. Working hypothesis: Impairment of the 5-HT system worsens ictal and post-ictal hypoventilation. A decrease in brain 5-HT has been shown to decrease the HCVR. We will increase or decrease brain 5-HT in mice and measure the frequency of spontaneous sudden death, and postictal changes in the HCVR. 3) Define the mechanisms by which whey prevents SUDEP. Working hypothesis: SUDEP risk is reduced by whey via an increase in brain 5-HT and/or CO2 chemoreception. We propose to examine whether whey is effective in preventing seizure-induced death in Scn8aN1768D, Kcna1-null and DBA/1 mice. We will examine whether whey prevents inhibition of the HCVR with seizures. We will examine which components have a protective effect on survival, and whether they act through changes in 5-HT. The expected outcome is that CO2 chemoreception will be established as central to the mechanisms of SUDEP and to how whey protects against it. The broader impact is that whey may be a new and safe approach to prevent SUDEP that targets mechanisms underlying postictal respiratory arrest.