Role of interneuronal and cholinergic defects in epileptic Arx mutant mice

描述（由申请人提供）：婴儿痉挛综合征（ISS）是一种毁灭性的癫痫，目前对其了解甚少。导致ISS的一个基因突变是ARX基因中的聚丙氨酸扩增。在Arx基因的第一个聚丙氨酸通道（Arx(GCG)7/Y）中添加7个GCG重复序列的转基因小鼠再现了在具有相同聚丙氨酸扩增的人类中观察到的许多癫痫发作和行为表型。这些小鼠最终可能被用于开发治疗ISS的疗法，但目前对这些小鼠癫痫的生理原因知之甚少。在Arx(GCG)7/Y小鼠中，胆碱能神经元和氨基丁酸能神经元均有显著的损失，但尚不清楚这些损失如何影响神经回路。在这些小鼠中，与癫痫发作有关的大脑区域也尚不清楚。这项工作的目的是通过识别与癫痫事件启动有关的大脑结构和神经网络异常，了解Arx(GCG)7/Y小鼠癫痫的原因。颅内脑电图记录将用于识别涉及的大脑结构

DESCRIPTION (provided by applicant): 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 abou 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.