Evaluation of Potential Mechanisms of SUDEP in a Mouse Model of Dravet Syndrome
Abstract number :
21
Submission category :
1. Basic Mechanisms / 1F. Other
Year :
2020
Submission ID :
2422370
Source :
www.aesnet.org
Presentation date :
12/5/2020 9:07:12 AM
Published date :
Nov 21, 2020, 02:24 AM
Authors :
Min-Jee Goh, University of Utah; Ana Beatriz DePaula-Silva - University of Utah; E. Jill Dahle - University of Utah; Glenna Wallis - University of Utah; Laura Bell - University of Utah; Cameron S. Metcalf - University of Utah;
Rationale:
Dravet syndrome (DS) is a genetic epilepsy disorder, the majority resulting from mutations in the sodium channel SCN1A gene. Sudden Unexplained Death in Epilepsy (SUDEP) occurs in up to 50% of DS patients. Risk factors for SUDEP have been identified, but mechanisms are not fully understood. We hypothesize that activated astrocyte-mediated post-ictal neuroinflammatory damage in the medulla may be involved. This neuroinflammatory damage is thought to disrupt medullary respiratory control centers, leading to respiratory dysfunction and sudden death. Glial fibrillary acidic protein (GFAP) is a marker of astrocyte activation and neuroinflammation. Understanding the mechanisms of SUDEP in DS is significant as it will allow us to begin to develop therapies to prevent this fatal outcome.
Method:
The objective of the study is to compare neuroinflammation in medullary respiratory control centers of heterozygous mice with a mutation (A1783V) in SCN1A (Het) to wild-type (WT) animals of two different ages, post-natal day 14 (P14) and P21-22 using GFAP expression as a marker of astrocyte-mediated inflammation. Brain tissue from Het and WT animals were sectioned and immunohistochemistry was performed to determine GFAP expression in three medullary respiratory control centers: the retrotrapezoid nucleus (RTN), nucleus tractus solitarius (NTS), and the rostral ventrolateral medulla (RVLM). Quantified GFAP fluorescence intensity was compared between the two animal groups.
Results:
There is a statistically significant difference in GFAP expression in the NTS of P14 Het animals compared to P14 WT animals (p = 0.0026). This differs from the RTN and RVLM of both P14 and P21-22 animals where no significant difference in GFAP expression was observed between Het and WT mice.
Conclusion:
These results suggest that activated astrocyte-mediated neuroinflammation may be involved in the inability of the NTS to properly regulate respiration and respond to post-ictal hypoxia, ultimately leading to the sudden death that occurs so commonly in Dravet Syndrome, particularly in younger subjects. The same conclusion cannot be made about the RTN or RVLM. Further studies are necessary to more definitively determine the role that neuroinflammation in the hindbrain plays in SUDEP in the DS population.
Funding:
:This work was supported by University of Utah College of Pharmacy.
Basic Mechanisms