Epilepsy is one of the most common neurological diseases in the world. This makes epilepsy a serious issue not only for those affected individuals and their families, but also for society and the medical profession. While many of the current treatments for epilepsy involve blocking the symptoms of the epilepsy, namely the seizures, there are few strategies that can ameliorate the ongoing reorganizational processes that are occurring in the epileptic brain. Therefore, elucidating the mechanisms responsible for this reorganization is vital for a better understanding of this process and for developing therapies that can ultimately prevent epilepsy. We have refined a rodent model of seizures using the chemoconvulsant, flurothyl. In this model, initial myoclonic jerk threshold, initial generalized seizure threshold, and two reorganizational/epileptogenic processes can be studied, 1) decreases in seizure threshold over 8 seizure trials and 2) alterations in seizure behavior, both of which occur over time. Our data suggest the hypothesis that there is significant genetic control of the processes underlying these reorganizational events observed in the repeated-flurothyl model as exemplified by differences observed between C57BL/6J and DBA/2J mice. Moreover, these traits segregate independently in C57BL/6J x DBA/2J (BXD) recombinant inbred (RI) lines. Thus, the goals of this proposal are to map quantitative trait loci (QTLs) in BXD animals that control each aspect of the flurothyl seizure characteristics observed, and determine the genetic and molecular pathways that mediate the reorganizational processes in the brain. We also will determine the neuroanatomical underpinnings of the reorganizational processes, which occur in the flurothyl model, through analysis of detailed neuroactivity maps in the brain, changes in brain circuitry following repeated seizures, and the role of BDNF in these processes. Lastly, we will utilize the extensive brain expression dataset in the genenetwork.org database to correlate differential gene expression in BXD brains with seizure phenotypes in an effort to identify potential biomarkers to predict the likelihood of seizure occurrence. The repeated-flurothyl model will allow for greater insight into the genetic control of the generalized seizure threshold and brain reorganization, and can also lead to the identification of QTLs (and the underlying genes) that are directly responsible for these processes, and move beyond studies that examine generalized seizure threshold solely. As a whole, these studies will provide greater insight into the process of brain reorganization from the genetic to the systems level.

Public Health Relevance

Epilepsy is one of the most common neurological diseases, affecting approximately 1 - 4% of the total population by 80 years of age. While many of the current treatments for epilepsy involve blocking the symptoms of the epilepsy through seizures suppression, no current therapies target the ongoing epileptogenesis/reorganization that occurs in the epileptic brain. Our project is designed to better understand processes that are involved in the reorganization of the brain that accounts for the differences in seizure traits in different strains of mice. Our goal, using the repeated flurothyl model in mice, is to identify gene(s) and molecular processes that are altered following repeated seizures, accounting for the brain reorganization that can occur in the epileptic brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS064283-02
Application #
8214513
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Whittemore, Vicky R
Project Start
2011-02-01
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
2
Fiscal Year
2012
Total Cost
$336,124
Indirect Cost
$83,924
Name
Albany Medical College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
190592162
City
Albany
State
NY
Country
United States
Zip Code
12208
Tuz, Karina; Bachmann-Gagescu, Ruxandra; O'Day, Diana R et al. (2014) Mutations in CSPP1 cause primary cilia abnormalities and Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy. Am J Hum Genet 94:62-72
Kadiyala, Sridhar B; Papandrea, Dominick; Herron, Bruce J et al. (2014) Segregation of seizure traits in C57 black mouse substrains using the repeated-flurothyl model. PLoS One 9:e90506
Tuz, Karina; Hsiao, Yi-Chun; Juarez, Oscar et al. (2013) The Joubert syndrome-associated missense mutation (V443D) in the Abelson-helper integration site 1 (AHI1) protein alters its localization and protein-protein interactions. J Biol Chem 288:13676-94