Preferential inactivation of Scn1a in parvalbumin interneurons increases seizure susceptibility.
Preferential inactivation of Scn1a in parvalbumin interneurons increases seizure susceptibility.
复制标题
在白蛋白中间神经元中SCN1a的优先失活会增加癫痫发作的敏感性。
DOI：
10.1016/j.nbd.2012.08.012
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发表时间：
2013-01
影响因子：
6.1
通讯作者：
Escayg A
中科院分区：
文献类型：
--
作者：
Dutton SB;Makinson CD;Papale LA;Shankar A;Balakrishnan B;Nakazawa K;Escayg A
电压门控钠通道(VGSCs)是电兴奋细胞产生和传播动作电位所必需的。编码Nav1.1VGSCα-亚基的SCN1a的显性突变是几种形式癫痫的基础，包括德拉韦综合征(DS)和遗传性癫痫伴热性惊厥(GEFS+)。对DS和GEFS+小鼠模型的电生理学分析导致了这样的假设，即SCN1A突变降低了皮层和海马区抑制性中间神经元的兴奋性。为了更直接地检测抑制性中间神经元和兴奋性锥体细胞在SCN1A型癫痫中的相对作用，我们首先用荧光免疫组织化学方法比较了P22小鼠抑制性小白蛋白中间神经元和兴奋性神经元中Nav1.1的表达。在海马区和大脑皮层，69%的Nav1.1免疫反应神经元也呈PV阳性。而CaMK2α免疫反应显示，在海马区和大脑皮层，分别有13%和5%的Nav1.1阳性细胞与兴奋性细胞共存。接下来，我们通过将杂合的Scn1a等位基因的小鼠分别与Ppp1r2-Cre或EMX1-Cre转基因系杂交，减少了Scn1a在部分中间神经元(主要是PV中间神经元)或兴奋细胞中的表达。在大脑皮层和海马区的中间神经元中，一个Scn1a等位基因的失活足以降低氟甲烷和高温诱导癫痫发作的阈值，而在兴奋性细胞中的失活不会改变阈值。中间神经元Scn1a表达减少也导致自发性癫痫的发生。这些发现为PV中间神经元在Scn1a源性癫痫发病机制中的重要作用提供了直接证据。
Voltage-gated sodium channels (VGSCs) are essential for the generation and propagation of action potentials in electrically excitable cells. Dominant mutations in SCN1A, which encodes the Nav1.1 VGSC α-subunit, underlie several forms of epilepsy, including Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+). Electrophysiological analyses of DS and GEFS+ mouse models have led to the hypothesis that SCN1A mutations reduce the excitability of inhibitory cortical and hippocampal interneurons. To more directly examine the relative contribution of inhibitory interneurons and excitatory pyramidal cells to SCN1A-derived epilepsy, we first compared the expression of Nav1.1 in inhibitory parvalbumin (PV) interneurons and excitatory neurons from P22 mice using fluorescent immunohistochemistry. In the hippocampus and neocortex, 69% of Nav1.1 immunoreactive neurons were also positive for PV. In contrast, 13% and 5% of Nav1.1 positive cells in the hippocampus and neocortex, respectively, were found to co-localize with excitatory cells identified by CaMK2α immunoreactivity. Next, we reduced the expression of Scn1a in either a subset of interneurons (mainly PV interneurons) or excitatory cells by crossing mice heterozygous for a floxed Scn1a allele to either the Ppp1r2-Cre or EMX1-Cre transgenic lines, respectively. The inactivation of one Scn1a allele in interneurons of the neocortex and hippocampus was sufficient to reduce thresholds to flurothyl- and hyperthermia-induced seizures, whereas thresholds were unaltered following inactivation in excitatory cells. Reduced interneuron Scn1a expression also resulted in the generation of spontaneous seizures. These findings provide direct evidence for an important role of PV interneurons in the pathogenesis of Scn1a-derived epilepsies.
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影响因子：
2.6
作者：
Li, Bing-Mei;Liu, Xiao-Rong;Liao, Wei-Ping
通讯作者：
Liao, Wei-Ping
影响因子：
2.7
作者：
Ma, JY;Leung, LS
通讯作者：
Leung, LS
影响因子：
14.5
作者：
Marco, P;Sola, RG;DeFelipe, J
通讯作者：
DeFelipe, J
DOI：
10.1073/pnas.0813330106
发表时间：
2009-03-10
影响因子：
11.1
作者：
Oakley, John C.;Kalume, Franck;Catterall, William A.
通讯作者：
Catterall, William A.
影响因子：
10.5
作者：
Boltor, Patrick F.;Carcani-Rathwell, Iris;Rutter, Michael
通讯作者：
Rutter, Michael