Infantile spasms syndrome (ISS) is a devastating form of epilepsy that is poorly understood. One genetic mutation leading to ISS is a polyalanine expansion in the ARX gene. A transgenic mouse with an addition of 7 GCG repeats into the 1st polyalanine tract of the Arx gene (Arx(GCG)7/Y) recapitulates much of the seizure and behavioral phenotype observed in humans with the same polyalanine expansion. These mice could ultimately be used to develop therapies to treat ISS, but very little is currently known about the physiological causes of epilepsy in these mice. Significant losses of both cholinergic and GABA-ergic neurons have been described in Arx(GCG)7/Y mice, but it is not known how these losses affect neural circuits. The brain regions involved in seizure onset in these mice are also not known. The goal of this work is to understand the causes of epilepsy in Arx(GCG)7/Y mice by identifying the brain structures and neural network abnormalities involved in initiating epileptic events. Intracranial EEG recordings will be used to identify brain structures involved in seizure onset in Arx(GCG)7/Y mice. Voltage-sensitive dye imaging and single cell physiology will be used to determine how losses of GABA-ergic and cholinergic neurons alter neural circuits in Arx(GCG)7/Y mice. Finally, Arx(GCG)7/Y mice will be treated with a cholinergic agonist to determine if the cholinergic neurotransmitter system is a potential therapeutic target in ISS patients. By identifying the mechanisms of seizures in this model, we will ultimately be able to develop new therapies to treat patients with ISS.

Public Health Relevance

Infantile spasms syndrome (ISS) is a devastating form of epilepsy that often leads to life long seizures and significant cognitive disabilities. One cause of ISS is a mutation in the ARX gene. A mouse with an Arx mutation has seizures and behavioral deficits similar to those occurring in humans with ISS. The proposed research will use a combination of electrophysiological approaches to understand the pathophysiology that causes epilepsy in these mice. Ultimately, this model can be used to develop therapies to treat ISS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32NS080556-03
Application #
8589017
Study Section
Special Emphasis Panel (ZRG1-F03B-A (20))
Program Officer
Whittemore, Vicky R
Project Start
2012-12-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
3
Fiscal Year
2014
Total Cost
$52,190
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Bourgeois, Elliot B; Johnson, Brian N; McCoy, Almedia J et al. (2014) A toolbox for spatiotemporal analysis of voltage-sensitive dye imaging data in brain slices. PLoS One 9:e108686