Contribution of the Cerebellar Cortex in Absence Seizure Formation in P/Q type Calcium Channel Mouse Models

小脑皮质在 P/Q 型钙通道小鼠模型失神发作形成中的作用

• 批准号: 223484474
• 负责人: Professorin Dr. Melanie D. Mark
• 金额: --
• 依托单位: Arbeitsgruppe Verhaltensneurobiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/223484474?language=en
• 关键词: Contribution; Cerebellar; Cortex; Absence; Seizure

Absence epilepsy is one feature of idiopathic generalized epilepsy (IGE), which accounts for 3-4% of all epileptic seizure disorders. Absence seizures, also known as petit mal seizures, are commonly characterized as an abrupt loss of consciousness and behavior arrest for several seconds accompanied by 3-4 Hz spike- and slow-wave discharges on electroencephalograms. However these seizures can lasts up to minutes in atypical absence epilepsy individuals. Although the etiology of IGEs can be complex, one specific type of IGE, childhood absence epilepsy, has been linked to mutations in several ion channels and in particular the P/Q-type calcium channel (Cav2.1). Spontaneous mutations in the P/Q type channel in mice have provided an essential tool for understanding the networks contributing to absence epilepsy. However more genetic tools are necessary to identify specific cellular and molecular pathways involved in absence epilepsy to provide better therapeutic options for suffering individuals. We established a mouse model for elucidating the cell-type specific function of P/Q type channels and demonstrated the functional and developmental role of the P/Q type channel in Purkinje and granule cells in the cerebellum. In these studies we found that the postnatal loss of the P/Q type calcium channels from either Purkinje or granule cells from the cerebellum was sufficient to cause ataxia, dyskinesia and absence seizures in mice. We will now use these established mouse lines to investigate the contribution of specific cerebellar neurons in the initiation and development of absence seizures. In addition we will develop optogenetic tools to identify the second messenger pathways involved in absence seizure formation, which may be useful therapeutic tools to eliminate absence seizures in humans.

失神性癫痫是特发性全身性癫痫（IGE）的特征之一，占所有癫痫发作疾病的3-4%。失神发作，也称为癫痫小发作，通常特征为意识突然丧失和行为停止数秒，伴有脑电图上3-4 Hz的尖峰和慢波放电。然而，在非典型失神癫痫患者中，这些癫痫发作可持续长达几分钟。虽然IGE的病因可能很复杂，但一种特殊类型的IGE，即儿童失神癫痫，与几种离子通道的突变有关，特别是P/Q型钙通道（Cav2.1）。小鼠P/Q型通道的自发突变为理解导致失神癫痫的网络提供了一个重要的工具。然而，需要更多的遗传工具来识别与失神癫痫相关的特定细胞和分子通路，以便为患有癫痫的个体提供更好的治疗选择。我们建立了一个阐明P/Q型通道的细胞类型特异性功能的小鼠模型，并证明了浦肯野细胞和小脑颗粒细胞中P/Q型通道的功能和发育作用。在这些研究中，我们发现出生后浦肯野细胞或小脑颗粒细胞的P/Q型钙通道的丢失足以引起小鼠共济失调、运动障碍和失神发作。我们现在将使用这些已建立的小鼠品系来研究特定小脑神经元在失神发作的起始和发展中的作用。此外，我们将开发光遗传学工具来识别参与失神发作形成的第二信使途径，这可能是消除人类失神发作的有用治疗工具。