Mechanisms by which T-type calcium channels increase seizure susceptibility

重要性-癫痫影响了美国约250万人。如果控制不当 通过抗癫痫药物，癫痫发作障碍可导致生活质量降低和生产力丧失。一 一类癫痫被称为特发性全身性癫痫（IGE），因为病因不明 癫痫发作可以改变整个大脑的活动（全身性）。虽然这种类型的 癫痫可以遗传，似乎有许多基因参与（多基因）。基因突变， 在IGE患者中发现了编码Cav3.2通道的CACNA 1H。 方法--这项研究将检验这些癫痫变异导致功能获得的假设， 或者通过改变Cav3.2通道活性，或者通过改变其在神经元中的表达。Cav3.2通道是一个 一种特殊类型的钙通道，可以在神经元的静息膜电位附近打开。这 钙离子进入可以通过两种重要的方式影响神经元，一种是使细胞膜脱钙， 一个神经元激发钠离子动作电位，另一个神经元增加神经元内的钙离子，第二信使 参与许多细胞过程的激活，如树突状分支。这些角色中 会受到癫痫变异的影响吗为了深入了解这一问题，目前的赠款将解决 以下具体目标：[1]建立Cav3.2通道在 神经元;和[2]确定Cav3.2的癫痫变体是否增加树突状分支， 这是否可以通过新的T通道拮抗剂逆转。用于解决这些问题的方法 重要的问题包括分子生物学，细胞生物学，荧光显微镜，电生理学， 药理学 影响-这些研究可能会通过揭示T的新作用来影响神经科学领域， 树突状分支和神经元兴奋性的通道，并通过验证新的拮抗剂。的 研究可能会产生临床影响：显示T通道拮抗剂逆转Cav3.2的作用。 树突发育的变异，从而为它们早期用于治疗癫痫提供了理论基础。

Significance -- Epilepsy affects about 2.5 million people in the United States. If not properly controlled by antiepileptic drugs, seizure disorders can lead to lower quality of life and loss of productivity. One class of epilepsy is called idiopathic generalized epilepsy (IGE), because the cause is not known (idiopathic) and the seizures can alter activity throughout the brain (generalized). Although this type of epilepsy can be inherited, there appear to be many genes involved (polygenic). Mutations in the gene, CACNA1H, which encodes the Cav3.2 channel, have been discovered in IGE patients. Approach -- This study will test the hypothesis that these epilepsy variants lead to a gain of function, either by altering Cav3.2 channel activity, or by altering its expression in neurons. Cav3.2 channels are a special class of calcium channel that can open near the resting membrane potential of neurons. This calcium entry can affect neurons in two important ways, one to depolarize the membrane and cause the neuron to fire sodium action potentials, and two, to increase calcium within the neuron, a 2nd messenger involved in the activation of many cellular processes such as dendritic arborization. Which of these roles is affected by epilepsy variants? To provide insights into this question, the present grant will address the following specific aims: [1] to establish the mechanisms by which Cav3.2 channels are trafficked in neurons; and [2] determine whether epilepsy variants of Cav3.2 increase dendritic arborization and whether this can be reversed by novel T-channel antagonists. The approaches used to address these important issues include molecular biology, cell biology, fluorescent microscopy, electrophysiology, and pharmacology. Impact -- These studies are likely to impact the field of neuroscience by uncovering novel roles of T- channels in dendritic arborization and neuronal excitability, and by validating novel antagonists. The studies will likely have a clinical impact: showing that T-channel antagonists reverse the effects of Cav3.2 variants on dendritic development, thereby providing the rationale for their early use to cure epilepsy.