Authors :
Presenting Author: Patrick Woller, – University of Cincinnati
McKenzie Rice, BS – Cincinnati Children's Hospital; Durgesh Tiwari, Ph.D. – Cincinnati Children's Hospital; Christina Gross, Ph.D. – Cincinnati Children's Hospital; Steven Crone, Ph.D. – Cincinnati Children's Hospital
Rationale:
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in individuals with epilepsy and may be caused by respiratory deficits. Abnormalities in the PI3K/mTOR signaling pathway contribute to seizure development and an increased risk of SUDEP. Forebrain structures can influence breathing, presumably through connections to brainstem respiratory centers, but whether altered mTOR signaling in the forebrain can lead to changes in breathing and/or respiratory arrest is still unknown.
Methods:
We used a genetic mouse model of SUDEP in which excitatory forebrain neurons lack PTEN (PTEN-CKO), an inhibitor of the mTOR pathway. Additionally, we developed a system for continuous recording (24 hours/day) of cortical electroencephalography (EEG), diaphragm electromyography (EMG), and video, along with analysis methods to assess breathing in PTEN-CKO (and control mice) prior to seizure onset, during or immediately post-seizure, throughout inter-ictal periods, and at the time of SUDEP.Results:
We found that diaphragm EMG recordings faithfully captured respiratory frequency and regularity, as well as detected respiratory features such as sighs, apneas, and irregular breathing comparable to plethysmography (a gold standard for noninvasive respiratory monitoring). Sleep state and movement detection could be automated using software to analyze EEG and video recordings, respectively. We detected irregular breathing and apneas in PTEN-CKO mice, even during inter-ictal periods. Hours before death, PTEN-CKO animals displayed decreased respiratory frequency and longer durations of inspiratory bursts, a dramatic increase in seizure frequency, and abnormal EEG spike activity. Terminal apnea preceded terminal asystole in all PTEN-CKO animals.Conclusions:
Our continuous monitoring system allows us to assess the onset and frequency of breathing abnormalities and spontaneous seizures in the weeks leading up to and including the death of PTEN-CKO mice. Our data indicate that changes in breathing patterns may predict SUDEP in mouse models of epilepsy.
Funding:
NIH Grant #R21NS121644-01A1
CURE Epilepsy Foundation "PI3K Signaling as a Novel Disease Mechanism-Based Target to Prevent or Reduce SUDEP"
T32 Grant NS007453