Genetic factors play a major role in the development of epilepsy. In fact, with recent advances in human genetics it is now clear that mutations resulting in ion channel dysfunction, neurotransmitter receptor alterations, or abnormal brain development can predispose an individual to seizure activity. In contrast to what is known about the genetics of seizure susceptibility, virtually nothing is known about mutations that confer seizure resistance. To address this problem, we propose an innovative strategy to identify genes that render an organism resistant to the development of seizure activity. By combining the expertise of an epilepsy laboratory (Dr. S.C. Baraban) with that of a zebrafish genetics laboratory (Dr. H. Baier), we plan to identify seizure resistance mutants using large-scale mutagenesis screening in zebrafish (Danio rerio). Identification of genetic determinants of seizure resistance could, ultimately, lead to novel gene-based approaches that are designed to prevent the initiation of epileptic activity and result in a """"""""seizure-free"""""""" life. Zebrafish mutagenesis screens have already identified mutations that define the function of hundreds of essential vertebrate genes. Here we propose to perform a highly selective functional screen in which behavioral and physiological measures are used to identify mutagenized zebrafish that are resistant to the development of seizure activity following exposure to a common convulsant agent (i.e., pentylenetetrazol).
In Aims I & II, we will identify seizure resistant fish by monitoring behavior and electrographic activity following exposure to pentylenetetrazol.
In Aim III, we will map, clone, and sequence the genes that confer seizure resistance to these fish. The results of this unique collaboration promise to provide new insights into the genetic factors that influence epilepsy, and will, perhaps, lead to a cure for this devastating neurological disorder.
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| Muto, Akira; Orger, Michael B; Wehman, Ann M et al. (2005) Forward genetic analysis of visual behavior in zebrafish. PLoS Genet 1:e66 |
| Levy, D E; Caronna, J J; Singer, B H et al. (1985) Predicting outcome from hypoxic-ischemic coma. JAMA 253:1420-6 |
