Role of interneuronal and cholinergic defects in epileptic Arx mutant mice

项目总结/摘要 婴儿痉挛综合征（ISS）是一种破坏性的癫痫形式，人们对此知之甚少。一个遗传 导致ISS的突变是ARX基因中的多聚丙氨酸扩增。一只转基因小鼠， GCG重复进入Arx基因的第一聚丙氨酸段（Arx（GCG）7/Y）重演了大部分癫痫发作， 在具有相同多聚丙氨酸扩增的人类中观察到的行为表型。这些老鼠最终可以 用于开发治疗ISS的疗法，但目前对ISS的生理原因知之甚少。 这些老鼠的癫痫胆碱能神经元和GABA能神经元的显著损失已经在 Arx（GCG）7/Y小鼠，但尚不清楚这些损失如何影响神经回路。大脑区域参与了 这些小鼠癫痫发作也是未知的。这项工作的目标是了解癫痫的原因 在Arx（GCG）7/Y小鼠中，通过鉴定参与启动的脑结构和神经网络异常， 癫痫事件。颅内EEG记录将用于识别癫痫发作涉及的大脑结构 Arx（GCG）7/Y小鼠。电压敏感染料成像和单细胞生理学将用于确定如何 GABA能神经元和胆碱能神经元的丧失改变了Arx（GCG）7/Y小鼠的神经回路。最后，Arx（GCG）7/Y小鼠 将接受胆碱能激动剂治疗，以确定胆碱能神经递质系统是否是一个潜在的 ISS患者的治疗目标。通过在这个模型中识别癫痫发作的机制，我们最终将 能够开发新的疗法来治疗ISS患者。

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.