Project 1
In this series of studies funded by the NIH, we generate sound-induced seizures in genetically-modified rats to study the acute and chronic effects of generalized tonic-clonic seizures (GTCSs) on cardiorespiratory physiology and the neural networks in the brainstem that control these functions.
Millions of people live with Epilepsy. Most patients respond well to anti-epileptic drugs (AEDs) that individually or in combination can prevent seizures from occurring. However, ~30% of patients diagnosed with Epilepsy do not respond well to AEDs and experience persistent seizures. These patients have intractable or drug-resistant epilepsy, and have much higher risk of sudden unexplained death in epilepsy (SUDEP).
The nature of SUDEP and how an otherwise healthy person living with epilepsy might unexpectedly pass away remains unclear. Data from in-patient monitoring units suggest that some patients that succumb to SUDEP show a stereotypic sequence of events that lead to death. This may include a seizure followed by generalized EEG suppression, ventilatory suppression, heart rate suppression, and then terminal apnea and terminal asystole. Here in the lab, we aim to study the consequences of individual or repeated seizures in rat models of epilepsy that we have genetically engineered to mimic aspects of the human disease.
Wireless EEG recordings from sound-induced seizures of varying severity in SSkcnj16-/- rats.
An SSkcnj16-/- rat exposed to 10 kHz tone experiences a GTCS with dramatic effects on breathing.
Rats with genetic mutations in the kcnj16 gene, which encodes the potassium ion channel subunit Kir5.1, are susceptible to sound-induced seizures. These unique rats exhibit many different phenotypes, but our interest is in their seizure disorder. A single exposure to a specific tone (10 kHz; 80 dB; 2 min) or mixed frequency sound (white noise; 80-100 dB; 2 min) is sufficient to elicit a GTCS. The effects of the sound-induced GTCS on breathing include a primary apnea and reduced breathing/heart rate for a few minutes after the seizure. However, if we give one seizure/day for up to 10 days, the effects of the seizure on breathing are more pronounced. In addition, the rats experience increased unexpected mortality.
Therefore, our central hypothesis is that repeated seizures induce progressive dysfunction in neural networks controlling cardiorespiratory functions to increase risk of unexpected, seizure-related death. Our current studies are focused on the mechanisms that may drive this progressive dysfunction, including a potential role for the brainstem serotonin (5-HT) system and/or neuroinflammation.