Weiergräber Marco, Henry Margit, Krieger Andreas, Kamp Marcel, Radhakrishnan Kayalvizhi, Hescheler Jürgen, Schneider Toni
Institute of Neurophysiology, University of Cologne, Köln, Germany.
Epilepsia. 2006 May;47(5):839-50. doi: 10.1111/j.1528-1167.2006.00541.x.
Recently the Ca(v)2.3 (E/R-type) voltage-gated calcium channel (VGCC) has turned out to be not only a potential target for different antiepileptic drugs (e.g., lamotrigine, topiramate) but also a crucial component in the pathogenesis of absence epilepsy, human juvenile myoclonic epilepsy (JME), and epileptiform activity in CA1 neurons. The aim of our study was to perform an electroencephalographic analysis, seizure-susceptibility testing, and histomorphologic characterization of Ca(v)2.3-/- mice to unravel the functional relevance of Ca(v)2.3 in ictogenesis.
Generalized and brain-specific Ca(v)2.3 knockout animals were analyzed for spontaneous epileptiform discharges by using both electrocorticographic and deep intracerebral recordings. In addition, convulsive seizure activity was induced by systemic administration of either 4-aminopyridine (4-AP; 10 mg/kg, i.p.) or pentylenetetrazol (PTZ; 80 mg/kg, s.c.) to reveal possible alterations in seizure susceptibility. Besides histomorphologic analysis, expression studies of other voltage-gated Ca2+ channels in Ca(v)2.3-/- brains were carried out by using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR).
Both electrocorticographic and deep intrahippocampal recordings exhibited no spontaneous epileptiform discharges indicative of convulsive or nonconvulsive seizure activity during long-term observation. Gross histology and expression levels of other voltage-gated Ca2+ channels remained unchanged in various brain regions. Surprisingly, PTZ-induced seizure susceptibility was dramatically reduced in Ca(v)2.3-deficient mice, whereas 4-AP sensitivity remained unchanged.
Ca(v)2.3 ablation results in seizure resistance, strongly supporting recent findings in CA1 neurons that Ca(v)2.3 triggers epileptiform activity in specialized neurons via plateau potentials and afterdepolarizations. We provide novel insight into the functional involvement of Ca(v)2.3 in ictogenesis and seizure susceptibility on the whole-animal level.
最近发现Ca(v)2.3（E/R型）电压门控钙通道（VGCC）不仅是不同抗癫痫药物（如拉莫三嗪、托吡酯）的潜在靶点，也是失神癫痫、人类青少年肌阵挛性癫痫（JME）发病机制以及CA1神经元癫痫样活动的关键组成部分。我们研究的目的是对Ca(v)2.3基因敲除小鼠进行脑电图分析、癫痫易感性测试和组织形态学特征分析，以阐明Ca(v)2.3在癫痫发生中的功能相关性。
通过皮层脑电图和深部脑内记录，对全身性和脑特异性Ca(v)2.3基因敲除动物的自发性癫痫样放电进行分析。此外，通过腹腔注射4-氨基吡啶（4-AP；10mg/kg）或皮下注射戊四氮（PTZ；80mg/kg）诱导惊厥性癫痫活动，以揭示癫痫易感性的可能变化。除了组织形态学分析外，还通过半定量逆转录-聚合酶链反应（RT-PCR）对Ca(v)2.3基因敲除小鼠脑内其他电压门控Ca2+通道进行表达研究。
在长期观察期间，皮层脑电图和海马深部记录均未显示出指示惊厥性或非惊厥性癫痫活动的自发性癫痫样放电。不同脑区的大体组织学和其他电压门控Ca2+通道的表达水平均未改变。令人惊讶的是，Ca(v)2.3基因缺陷小鼠对PTZ诱导的癫痫易感性显著降低，而对4-AP的敏感性保持不变。
Ca(v)2.3基因敲除导致癫痫抵抗，有力地支持了最近在CA1神经元中的发现，即Ca(v)2.3通过平台电位和后去极化触发特定神经元的癫痫样活动。我们在整体动物水平上为Ca(v)2.3在癫痫发生和癫痫易感性中的功能参与提供了新的见解。
