Role of interneuronal and cholinergic defects in epileptic Arx mutant mice

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Project Summary/Abstract 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.