Developmental regulation of K+ M-current in brain

大脑 K M 电流的发育调节

• 批准号: 7068046
• 负责人: MELANIE K TALLENT
• 金额: $ 26.65万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-18 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7068046
• 关键词: action potentials; confocal scanning microscopy; developmental neurobiology; electrical potential; epilepsy; gene expression; gene mutation; hippocampus; immunocytochemistry; laboratory rat; male; neocortex; neural transmission; neurons; pathologic process; potassium channel; protein localization

DESCRIPTION (provided by applicant): The M-current (IM) is a voltage-dependent K+ current that is important in regulating neuronal excitability. M-channels have slow opening and closing kinetics and do not deactivate. They are partially open in the range of the resting membrane potential and open further upon depolarization. Thus they act as a "clamp" to keep a neuron below its threshold for firing, and profoundly influence the response of a neuron to synaptic input. KCNQ subtypes of K+ channels have been shown to underlie IM; in the brain KCNQ2/KCNQ3 and KCNQ3/KCNQ5 heterotetramers appear to make up native M-channels. Interestingly, mutations in KCNQ subunits have been shown to underlie several human genetic diseases. Mutations in KCNQ2 and KCNQ3 subunits resulting in dysfunctional channels are linked to a congenital epilepsy, benign familial neonatal convulsions (BFNC). This epilepsy is characterized by generalized seizures that appear shortly after birth and spontaneously remit weeks to months later. However a higher incidence of adult epilepsy is seen in these patients. This suggests that IM may be especially critical in immature brain. Our major hypothesis is as follows. In normal human brain a critical level of IM is reached prior to an increase in cortical excitability that appears shortly after birth. This important inhibitory mechanism prevents seizure generation. However, when one of the channels is mutated, as in BFNC, a mismatch appears between expression of appropriate current density and the increase in cortical excitability. This corresponds to the onset of seizures in this disease. Eventually, the "safety threshold" is reached by the mutated channels, but it is developmentally delayed compared to normal channels. Once this safety level is reached, seizures remit. We have designed an integrative approach that it allows us to directly relate developmental changes in subunit expression patterns, IM levels, and IM contribution to both normal and epileptic brain function. The project described in this application should clarify the pathophysiology of this disease and provide insight into the function of IM, that is an important inhibitory regulator in immature brain.

描述(申请人提供)：M-电流(IM)是一种电压依赖的K+电流，在调节神经元兴奋性方面很重要。M-通道具有缓慢的开启和关闭动力学，并且不会失活。它们在静息膜电位范围内部分开放，并在去极化时进一步开放。因此，它们起到了“钳子”的作用，将神经元保持在放电阈值以下，并深刻地影响神经元对突触输入的反应。K+通道的KCNQ亚型被证明是IM的基础；在大脑中，KCNQ2/KCNQ3和KCNQ3/KCNQ5异构体似乎构成了天然的M通道。有趣的是，KCNQ亚单位的突变已被证明是几种人类遗传病的基础。KCNQ2和KCNQ3亚基突变导致的通道功能障碍与先天性癫痫、良性家族性新生儿惊厥(BFNC)有关。这种癫痫的特征是出生后不久出现全身性癫痫发作，并在几周到几个月后自发缓解。然而，成人癫痫的发病率在这些患者中较高。这表明IM在不成熟的大脑中可能尤其关键。 我们的主要假设如下。在正常人脑中，IM在出生后不久出现的皮质兴奋性增加之前就达到了一个临界值。这一重要的抑制机制阻止了癫痫的产生。然而，当其中一个通道发生突变时，就像在BFNC中一样，适当的电流密度的表达与皮质兴奋性的增加之间出现了不匹配。这与这种疾病的癫痫发作相对应。最终，突变的通道达到了“安全阈值”，但与正常通道相比，它的发育延迟了。一旦达到这个安全水平，癫痫发作就会缓解。我们设计了一种综合的方法，使我们能够直接将亚单位表达模式、IM水平以及IM对正常和癫痫脑功能的贡献的发育变化联系起来。本申请中描述的项目应该阐明这种疾病的病理生理学，并提供对IM的功能的洞察，IM是未成熟大脑中重要的抑制性调节因子。