Developmental regulation of K+ M-current in brain

大脑 K M 电流的发育调节

• 批准号: 6950290
• 负责人: MELANIE K TALLENT
• 金额: $ 27.06万
• 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/6950290
• 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（由申请人提供）：M 电流（IM）是电压依赖性 K+ 电流，对于调节神经元兴奋性很重要。 M 通道具有缓慢的打开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，它们充当“钳子”，将神经元保持在其放电阈值以下，并深刻影响神经元对突触输入的反应。 K+ 通道的 KCNQ 亚型已被证明是 IM 的基础；在大脑中，KCNQ2/KCNQ3 和 KCNQ3/KCNQ5 异四聚体似乎构成了天然 M 通道。有趣的是，KCNQ 亚基的突变已被证明是多种人类遗传疾病的基础。 KCNQ2 和 KCNQ3 亚基突变导致通道功能障碍，与先天性癫痫、良性家族性新生儿惊厥 (BFNC) 有关。这种癫痫的特点是出生后不久出现全身性癫痫发作，并在数周至数月后自发缓解。然而，这些患者的成人癫痫发病率较高。这表明 IM 对于未成熟的大脑可能尤其重要。 我们的主要假设如下。在正常人脑中，在出生后不久出现的皮层兴奋性增加之前，IM 就达到了临界水平。这种重要的抑制机制可以防止癫痫发作。然而，当其中一个通道发生突变时，如在 BFNC 中，适当电流密度的表达与皮质兴奋性的增加之间会出现不匹配。这对应于这种疾病的癫痫发作。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。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方法，它使我们能够直接将亚基表​​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，并深入了解 IM 的功能，IM 是未成熟大脑中的重要抑制调节因子。