Direct Imaging of Hippocampal Epileptiform Calcium Motifs Following Kainic Acid Administration in Freely Behaving Mice.
Direct Imaging of Hippocampal Epileptiform Calcium Motifs Following Kainic Acid Administration in Freely Behaving Mice.
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DOI：
10.3389/fnins.2016.00053
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发表时间：
2016
影响因子：
4.3
通讯作者：
Bonaventure P
中科院分区：
文献类型：
--
作者：
Berdyyeva TK;Frady EP;Nassi JJ;Aluisio L;Cherkas Y;Otte S;Wyatt RM;Dugovic C;Ghosh KK;Schnitzer MJ;Lovenberg T;Bonaventure P
长时间暴露于异常高的钙浓度被认为是癫痫患者海马损伤的核心机制;然而，没有先前的研究表征了癫痫发作期间在活的、完整的海马中的钙活性。我们已经直接调查了这种可能性相结合的全脑脑电图（EEG）的测量与显微内镜钙成像的锥体细胞在CA 1海马区的自由行为的小鼠治疗的促惊厥红藻氨酸（KA）。我们观察到，KA管理导致癫痫样钙活动的系统模式：一系列大规模的，增强闪烁的钙荧光增加，同时与一组低振幅的EEG波形。伴随着细胞钙水平的稳定增加（相对于基线增加>5倍），随后出现强烈的钙扩散波，其特征是钙荧光的全球平均强度增加218%（n = 8，范围[114-349%]，p < 10 - 4; t检验）。该波没有一致的EEG表型，发生在运动性惊厥发作之前。在用2种不同的促惊厥剂N-甲基-D-天冬氨酸（NMDA）和戊四氮（PTZ）处理的动物中也观察到钙活性的类似变化，表明钙动力学的测量变化是癫痫发作活动的特征，而不是KA特异性病理学。此外，尽管降低了KA诱导癫痫发作的行为严重程度，但抗惊厥药物丙戊酸盐（VA，300 mg/kg）并未改变观察到的钙动力学异常。这些结果证实了惊厥性运动性癫痫发作前存在病理性钙活动，并支持钙作为连接癫痫发作与随后细胞损伤的途径中的候选信号分子。将体内钙成像与癫痫发作的传统评估相结合可能会增加药理学干预的可翻译性，从而产生旨在靶向和消除电和钙兴奋异常模式的新型药物筛选范式和治疗方法。
Prolonged exposure to abnormally high calcium concentrations is thought to be a core mechanism underlying hippocampal damage in epileptic patients; however, no prior study has characterized calcium activity during seizures in the live, intact hippocampus. We have directly investigated this possibility by combining whole-brain electroencephalographic (EEG) measurements with microendoscopic calcium imaging of pyramidal cells in the CA1 hippocampal region of freely behaving mice treated with the pro-convulsant kainic acid (KA). We observed that KA administration led to systematic patterns of epileptiform calcium activity: a series of large-scale, intensifying flashes of increased calcium fluorescence concurrent with a cluster of low-amplitude EEG waveforms. This was accompanied by a steady increase in cellular calcium levels (>5 fold increase relative to the baseline), followed by an intense spreading calcium wave characterized by a 218% increase in global mean intensity of calcium fluorescence (n = 8, range [114–349%], p < 10−4; t-test). The wave had no consistent EEG phenotype and occurred before the onset of motor convulsions. Similar changes in calcium activity were also observed in animals treated with 2 different proconvulsant agents, N-methyl-D-aspartate (NMDA) and pentylenetetrazol (PTZ), suggesting the measured changes in calcium dynamics are a signature of seizure activity rather than a KA-specific pathology. Additionally, despite reducing the behavioral severity of KA-induced seizures, the anticonvulsant drug valproate (VA, 300 mg/kg) did not modify the observed abnormalities in calcium dynamics. These results confirm the presence of pathological calcium activity preceding convulsive motor seizures and support calcium as a candidate signaling molecule in a pathway connecting seizures to subsequent cellular damage. Integrating in vivo calcium imaging with traditional assessment of seizures could potentially increase translatability of pharmacological intervention, leading to novel drug screening paradigms and therapeutics designed to target and abolish abnormal patterns of both electrical and calcium excitation.