January 25, 2021

Screening of Genetically Diverse Mice Identifies Novel Rodent Models of Diverse Epilepsy Outcomes

Funded by the generosity of families who have experienced a loss due to SUDEP.

Key Points:

  • CURE Epilepsy Taking Flight Award grantee Dr. Bin Gu and colleagues used genetically diverse mouse strains to identify those that vary in seizure susceptibility, seizure spread, seizure development, and sudden unexpected death in epilepsy (SUDEP).
  • Initial screening of these mice identified four different genetic strains that suddenly and unpredictably died after inducing a single seizure, suggesting these mice may represent novel models for studying SUDEP.
  • Further genetic characterization of these four mouse strains should provide valuable insights into the underlying genetic risk factors for SUDEP.

Deep Dive:

Dr. Bin Gu, PhD

Dr. Bin Gu, PhD

SUDEP is the sudden, unexpected death of someone with epilepsy who otherwise appears healthy. To facilitate an understanding of the complex genetic basis of SUDEP, studies need to use genetically diverse mouse populations [1,2], such as the “Collaborative Cross” [3,4], which can help identify different genetic risk factors that control SUDEP susceptibility.

With the help of a CURE Epilepsy Taking Flight Award, Dr. Bin Gu and his colleagues in the laboratories of Drs. Ben Philpot and Fernando Pardo-Manuel de Villena at the University of North Carolina at Chapel Hill used Collaborative Cross mice to identify mouse strains that were more likely to have seizures, were more prone to having subsequent seizures, were more susceptible to having their seizures spread throughout the brain and were especially vulnerable to SUDEP [5].

The researchers screened mice from this population to identify candidate genes and genetic variants linked to many key symptoms of epilepsy. For example, within this population of mice, when Dr. Gu induced epilepsy, he observed that some mouse strains were resistant to developing epilepsy, whereas others were more susceptible. Identifying the genetics of the resistant strains is important for understanding the mechanisms underlying seizures and developing new ways of stopping seizures before full-blown epilepsy develops.

Among the groups of mice that Dr. Gu studied, four strains of mice died suddenly after a single seizure that was not fatal in “normal” mice. Although the precise cause of sudden death in these mice is currently unknown, the specific strains may eventually provide important clues to the causes of SUDEP in humans.

Dr. Gu’s upcoming research will focus on characterizing these “pro-SUDEP” strains, identifying those genes that control SUDEP susceptibility and resistance and studying the biological causes, including cardiac and respiratory events, that can provoke SUDEP. Such an understanding will hopefully lead to effective strategies to prevent SUDEP.

By providing Dr. Gu with critical initial funding for his research through a Taking Flight Award, CURE Epilepsy has also helped advance Dr. Gu’s career. He will soon establish his own independent lab as an Assistant Professor of Neuroscience at Ohio State University, where he will continue to pursue his passion for epilepsy research.

Dr. Bin Gu is a postdoctoral fellow at the University of North Carolina at Chapel Hill.

Literature Cited
[1] Saul, M.C. et al. High-diversity mouse populations for complex traits. Trends Genet. 2019; 35(7): 501-514.
[2] Bogue, M.A. et al Collaborative cross and diversity outbred data resources in the mouse phenome database. Mamm. Genome 2015; 26(9-10): 511-520.
[3] Churchill, G.A. et al. Complex Trait Consortium. The collaborative cross, a community resource for the genetic analysis of complex traits. Nature Genetics 2004; 36(11): 1133-1137.
[4] Srivastava, A. et al. Genomes of the mouse collaborative cross. Genetics 2017; 206(2): 537-556.
[5] Gu, B. et al. Collaborative cross mice reveal extreme epilepsy phenotypes and genetic loci for seizure susceptibility. Epilepsia 2020; 61(9): 2010-2021.

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