Experimentally Induced Convulsive Seizures Are Modulated in Part by Zinc Ions through the Pharmacoresistant Cav2.3 Calcium Channel.
Experimentally Induced Convulsive Seizures Are Modulated in Part by Zinc Ions through the Pharmacoresistant Cav2.3 Calcium Channel.
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DOI：
10.33594/000000213
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发表时间：
2020-02-19
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影响因子：
--
通讯作者：
Schneider, Toni
中科院分区：
文献类型：
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作者：
Alpdogan, Serdar;Neumaier, Felix;Schneider, Toni
背景/目的：仍然在 1999 年，首次发表了药物耐药性 Cav2.3 钙通道参与癫痫发作产生的提示，因为来自斯特拉斯堡的遗传失神性癫痫大鼠 (GAERS) 的大脑中 alpha1E (Cav2.3) 和 alpha1G (Cav3.1) 的转录物发生了变化。接下来，通过使用4-氨基吡啶、戊四唑、N-甲基-D-天冬氨酸和红藻氨酸诱导实验性惊厥性癫痫发作，对缺乏Cav2.3的小鼠的癫痫易感性进行了详细分析。此外，γ-羟基丁内酯用于诱导非惊厥性失神发作。对于所有测试的物质，Cav2.3 活性小鼠与敲除小鼠的不同之处在于，对于惊厥性癫痫发作，耐药通道的删除有利于实验诱导癫痫发作期间的结果 [1]。抗癫痫药物拉莫三嗪可降低 Cav2.3 活性小鼠的癫痫发作活动，但会增加 Cav2.3 缺陷小鼠的癫痫发作活动。在体内，Cav2.3 必须受到内源性微量金属阳离子（Zn2+ 和 Cu2+）的严格控制。它们中的任何一个，特别是 Cu2+ 的动态平衡失调，可能会严重改变 Cav2.3 的调节及其对 Ca2+ 电导的活性，从而可能将海马和新皮质信号转变成低兴奋或高兴奋。方法：为了通过遥测脑电图记录研究红藻氨酸产生高兴奋的机制，测试了小鼠对神经元变化的敏感性。 （脑室内）微量金属阳离子 Zn2+ 的浓度。由于血脑屏障限制了生物可利用的 Zn2+ 或 Cu2+ 进入大脑的分布，我们在存在 1 mM 组氨酸作为载体的情况下，在脑室内注射微摩尔 Zn2+ 离子，并比较对两种基因型的行为和脑电图活动的影响。 结果：Cav2.3 活性小鼠的红藻氨酸癫痫发作比 KO 小鼠更严重，并且组氨酸减少 正常小鼠的癫痫发作严重程度，但 Cav2.3 缺陷小鼠的癫痫发作严重程度则不然。令人惊讶的是，Zn2+ 加组氨酸与仅红藻氨酸对照类似，Cav2.3 活性小鼠比缺陷小鼠的癫痫发作更严重。结论：Cav2.3 代表一个重要的 Zn2+ 敏感靶标，可用于调节惊厥性癫痫发作。
BACKGROUND/AIMS: Still in 1999 the first hints were published for the pharmacoresistant Cav2.3 calcium channel to be involved in the generation of epileptic seizures, as transcripts of alpha1E (Cav2.3) and alpha1G (Cav3.1) are changed in the brain of genetic absence epilepsy rats from Strasbourg (GAERS). Consecutively, the seizure susceptibility of mice lacking Cav2.3 was analyzed in great detail by using 4-aminopyridine, pentylene-tetrazol, N-methyl-D-aspartate and kainic acid to induce experimentally convulsive seizures. Further, gamma-hydroxybutyrolactone was used for the induction of non-convulsive absence seizures. For all substances tested, Cav2.3-competent mice differed from their knockout counterparts in the sense that for convulsive seizures the deletion of the pharmacoresistant channel was beneficial for the outcome during experimentally induced seizures [1]. The antiepileptic drug lamotrigine reduces seizure activity in Cav2.3-competent but increases it in Cav2.3-deficient mice. In vivo, Cav2.3 must be under tight control by endogenous trace metal cations (Zn2+ and Cu2+). The dyshomeostasis of either of them, especially of Cu2+, may alter the regulation of Cav2.3 severely and its activity for Ca2+ conductance, and thus may change hippocampal and neocortical signaling to hypo- or hyperexcitation.METHODS: To investigate by telemetric EEG recordings the mechanism of generating hyperexcitation by kainate, mice were tested for their sensitivity of changes in neuronal (intracerebroventricular) concentrations of the trace metal cation Zn2+. As the blood-brain barrier limits the distribution of bioavailable Zn2+ or Cu2+ into the brain, we administered micromolar Zn2+ ions intracerebroventricularly in the presence of 1 mM histidine as carrier and compared the effects on behavior and EEG activity in both genotypes.RESULTS: Kainate seizures are more severe in Cav2.3-competent mice than in KO mice and histidine lessens seizure severity in competent but not in Cav2.3-deficient mice. Surprisingly, Zn2+ plus histidine resembles the kainate only control with more seizure severity in Cav2.3-competent than in deficient mice.CONCLUSION: Cav2.3 represents one important Zn2+-sensitive target, which is useful for modulating convulsive seizures.