Respiratory defects in an animal model of DEPDC5-related epilepsy and SUDEP
Abstract number :
1.451
Submission category :
1. Basic Mechanisms / 1F. Other
Year :
2022
Submission ID :
2232856
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:27 AM
Authors :
Hsin-Yi Kao, PhD – University of Michigan; Yilong yao, MD, PhD – University of Michigan; tao Yang, Ph.D – University of Michigan; Nurun Nahar Borna, MD, PhD – University of Michigan; peng Li, Ph.D – Univeristy of Michigan; Yu Wang, MD, PhD – University of Michigan
This is a Late Breaking abstract
Rationale: DEPDC5 is one of the most common causative genes in refractory epilepsy, and its loss-of-function mutations are also associated with sudden unexpected death in epilepsy (SUDEP). However, the underlying mechanism remains unclear because of the lack of an animal model that recapitulates both seizure and SUDEP phenotypes. In addition, it is unclear which specific cell type with DEPDC5 mutation leads to epilepsy and SUDEP and whether brainstem or/and cardiac defects contribute to SUDEP.
Methods: Using Rbp4-Cre, Nkx2.1-Cre, and Aldh1l1-CreERT2 transgenic mice, we respectively deleted DEPDC5 in a subpopulation of forebrain excitatory neurons, medial ganglionic eminence (MGE)-derived interneurons, and astrocytes. We used 24/7 video-EEG to monitor seizures to determine which cell lineage is sufficient and necessary to generate seizures. We then used concurrent EEG, cardiac, and respiratory monitoring to determine whether cardiac failure or respiratory arrest is involved in SUDEP. Finally, we studied the baseline respiratory function in SUDEP animals.
Results: We showed that DEPDC5 deletion in excitatory neurons in cortical layer 5 and dentate gyrus, but not in interneurons or astrocytes, is sufficient to cause frequent seizures and SUDEP. We observed that post-ictal generalized EEG suppression (PGES), particularly the delta and theta frequency bands, is a reliable marker for impending death. Surprisingly, these animals also showed progressive respiratory dysfunction.
Conclusions: Our studies provided a framework to further investigate the pathogenic network of DEPDC5-related epilepsy and SUDEP at molecular, cellular, and circuit levels.
Funding: U54NS117170, R01NS113824
Basic Mechanisms