Altered functions of ion channels, membrane receptors and neuronal networks associated with thalamocortical dysrhythmia syndrome.

与丘脑皮质心律失常综合征相关的离子通道、膜受体和神经元网络的功能改变。

• 批准号: 353966806
• 负责人: Professor Dr. Thomas Budde
• 金额: --
• 依托单位: Consejo Nacional de Investigaciones Científicas y Técnicas
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/353966806?language=en
• 关键词: Altered; functions; ion; channels; membrane

Thalamic abnormalities are common in neurological and psychiatric diseases (e. g., absence epilepsy, cocaine abuse). Based on the presence of slow delta and theta range bursting during wakefulness they are referred to as thalamocortical dysrhythmia syndromes. A hyperpolarized membrane potential of thalamocortical (TC) neurons is suggested to be the basis for aberrant burst activity. Neuronal hyperpolarization may occur by excess inhibition, deafferentation or block of NMDA receptors. However sensory deprivation and enhanced function of K+ channels, both potentially inducing membrane hyperpolarizations, have not been considered yet. Members of the K2P channel family crucially contribute to the generation of the hyperpolarized resting membrane potential in neurons. In order to be able to fully address the possible contribution of K2P channels to thalamocortical dysrhythmia, it is necessary to characterize the cellular signaling pathways modulating these channels in different thalamic cell types. Concerning this aspect, information is completely missing for GABAergic thalamic neurons (local interneurons; neurons of the reticular thalamic nucleus, NRT).The aims of the project are: (1) To determine the function of K2P channels in GABAergic thalamic neurons. (2) To determine the influence of psychostimulants and K2P channel activators / inhibitors on cellular and network activity. Since psychostimulants act via the increased availability of monoamines, especially dopamine, we will analyze dopaminergic pathways. (3) To determine the role of K2P channels in sensory deprivation as a new model of thalamocortical dysrhythmia based on deafferentation.The experimental approach will be: (1) PCR and immunohistochemical staining will be used to determine the expression and location of ion channels and membrane receptors. (2) Whole-cell patch-clamp recordings will be performed to determine electrophysiological and pharmacological properties of ion channels and membrane receptors in different thalamic cell types. GABAergic neurons will be directly targeted in knock-in mice expressing enhanced green fluorescent protein (EGFP) under the control of the glutamate decarboxylase 67 promotor (GAD67-EGFP). (3) Network activity will be addressed by performing local field potential (LFP) recordings in horizontal thalamic slices and thalamocortical slices of the somatosensory system (i.e., containing the ventrobasal thalamic complex; NRT; primary somatosensory cortex). (4) System function will be determined by combining LFP / single unit recordings in the somatosensory system and behavioral analysis in vivo. (5) As experimental animal models K2P channel knock out mice and unilateral sensory deprivation in mice by trimming of whiskers will be used.The results of the proposed study will help to determine new functional roles and possible pathological influences of K2P channels and their therapeutic potential in thalamocortical dysrhythmia syndromes.

丘脑异常在神经和精神疾病中很常见（例如，缺席癫痫，可卡因滥用）。基于在清醒期间慢速的三角洲和theta范围的存在，它们被称为丘脑皮质心律失常综合征。丘脑皮质（TC）神经元的超极化膜电位被认为是异常爆发活性的基础。神经元超极化可能通过过量的抑制作用，断层或NMDA受体的阻滞而发生。然而，尚未考虑感觉剥夺和K+通道的增强功能，两者都可能引起膜超极化。 K2P通道家族的成员至关重要地有助于神经元中超极化的静膜电位的产生。为了能够充分解决K2P通道对丘脑皮质动力学的可能贡献，有必要表征在不同丘脑细胞类型中调节这些通道的细胞信号通路。关于这一方面，GABA能丘脑神经元完全缺少信息（局部神经元；网状丘脑核的神经元，NRT）。该项目的目的是：（1）确定K2P通道在GABA>的丘脑神经元中的功能。 （2）确定心理刺激剂和K2P通道激活剂 /抑制剂对细胞和网络活性的影响。由于精神刺激药通过增加单胺的可用性，尤其是多巴胺的作用，因此我们将分析多巴胺能途径。 （3）确定K2P通道在感觉剥夺中的作用，作为基于脱落的丘脑皮质性运动障碍的新模型。实验方法将是：（1）PCR和免疫组织化学染色将用于确定离子通道和膜受体的表达和位置。 （2）将进行全细胞斑块钳记录，以确定不同丘脑细胞类型中离子通道和膜受体的电生理和药理特性。 GABA能神经元将直接靶向在谷氨酸脱羧酶67启动子（GAD67-EGFP）控制下表达增强绿色荧光蛋白（EGFP）的敲门小鼠。 （3）将通过在水平丘脑切片中执行局部场电位（LFP）记录来解决网络活动，并在体感系统的丘脑皮质切片中（即包含腹侧丘脑复合物； NRT; NRT; NRT; tripers somposensory Cortex; trice thalamoforical slices''。 （4）系统函数将通过在体体系统中结合LFP /单个单位记录和体内行为分析来确定。 （5）作为实验动物模型，K2P通道将通过修剪晶须的小鼠敲除小鼠和单侧感觉剥夺。拟议的研究的结果将有助于确定K2P通道的新功能作用和可能的病理影响，并可能对丘脑皮质运动障碍症的治疗潜力及其治疗潜力。