Sunday, May 11, 2025
5/11/2025
Serotonergic circuit mechanisms in postictal recovery and arousal - ABSTRACT Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. SUDEP is second only to stroke in years of potential life lost to neurological disease and is a major public health problem. Several etiologies have been proposed for SUDEP including cardiac and respiratory dysregulation. Another that is postulated is impaired arousal. Seizures impair arousal. Among arousal stimuli, one that may be particularly relevant to SUDEP is CO2. CO2 rises following seizures and is part of the seizure cessation mechanism. Seizures are frequently associated with ictal and post-ictal central and obstructive apneas. Apnea further exacerbates the accumulation of CO2. Impairment of CO2- arousal is proposed as an etiological factor in another sudden death entity, sudden infant death syndrome, which has many parallels with SUDEP. We discovered that seizures impaired CO2-arousal in seizure naïve mice and those that do not have a particularly profound death rate. Whether this is true in mouse models with strong SUDEP phenotypes is unknown. Thus, our goal in this proposal is to determine how seizures in different sleep states impair CO2-arousal in mouse models of temporal lobe epilepsy (TLE) and the genetic epileptic encephalopathy, Dravet Syndrome (DS). In Aim 1 we will determine the extent to which CO2-arousal is impaired in epilepsy models. We will focus on the pilocarpine-TLE model as many patients that die of SUDEP have TLE, and the DS model, as patients with DS have a disproportionately high SUDEP risk. We will also determine whether simply having epilepsy in these models impairs CO2-arousal as a potential easily measurable biomarker for SUDEP risk. In Aim 2 we will determine whether neuronal function, assessed via fiber photometry, of arousal system components in the dorsal raphe nucleus and parabrachial nucleus, two important contributors to sleep-wake regulation and key nodes in CO2-arousal, is impaired by seizures and epilepsy. In Aim 3 we will determine whether optogenetically stimulating a DRN-PBN circuit in DS mice, using a novel mouse model, prior to seizures prevents seizure-induced death lending direct insights into possible therapeutic measures. Since the models employed have known death rates, we will be able to compare findings between mice that die and those that survive making these studies more relevant to SUDEP. Combining these findings with our previous work, we will have a powerful, rigorous, translatable approach to identify convergent and divergent mechanisms across models for how impaired CO2-arousal in epilepsy contributes to SUDEP risk. We expect to be able to leverage these mechanisms to identify at-risk individuals and reduce death from this devastating disease.
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