Developmental regulation of K+ M-current in brain

描述（由申请人提供）：m电流（IM）是一种电压依赖性的K+电流，在调节神经元兴奋性方面很重要。m通道具有缓慢的打开和关闭动力学，并且不会失效。它们在静息膜电位范围内部分开放，在去极化时进一步开放。因此，它们就像一个“夹子”，使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的m通道。有趣的是，KCNQ亚基的突变已被证明是几种人类遗传疾病的基础。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。这种癫痫的特点是出生后不久出现全身性癫痫发作，几周到几个月后自然缓解。然而，这些患者的成人癫痫发病率较高。这表明，IM可能在未成熟的大脑中尤为重要。

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.