Nav1.1 haploinsufficiency in excitatory neurons ameliorates seizure-associated sudden death in a mouse model of Dravet syndrome.
Nav1.1 haploinsufficiency in excitatory neurons ameliorates seizure-associated sudden death in a mouse model of Dravet syndrome.
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DOI：
10.1093/hmg/ddt331
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发表时间：
2013-12-01
影响因子：
3.5
通讯作者：
Yamakawa K
中科院分区：
文献类型：
--
作者：
Ogiwara I;Iwasato T;Miyamoto H;Iwata R;Yamagata T;Mazaki E;Yanagawa Y;Tamamaki N;Hensch TK;Itohara S;Yamakawa K
Dravet综合征是一种严重的癫痫性脑病，主要由编码电压门控钠通道Nav1.1的SCN 1A基因的杂合突变引起。我们先前报道了Nav1.1在小鼠小清蛋白（PV）阳性抑制性中间神经元中的密集定位以及Nav1.1缺陷小鼠中这些神经元的异常放电。在本研究中，我们研究了选择性Nav1.1缺失小鼠的整体抑制性神经元，前脑兴奋性神经元或PV细胞的生理后果，使用囊泡GABA转运蛋白（VGAT）-Cre，空气门同源物1（Emx 1）-Cre或PV-Cre重组酶驱动程序。我们表明，选择性Nav1.1删除使用VGAT-Cre导致癫痫发作和过早死亡，出乎意料的是更严重的比观察到的组成Nav1.1缺陷小鼠。使用Emx 1-Cre的Nav1.1缺失不会在小鼠中引起任何明显的异常;然而，使用Emx 1-Cre的额外Nav1.1缺失挽救了使用VGAT-Cre驱动的Nav1.1缺失观察到的严重致死性。除了PV中间神经元中的主要表达外，我们还在兴奋性神经元的亚群中检测到Nav1.1，包括内鼻-海马投射神经元、新皮质层V兴奋性神经元的亚群和丘脑-皮质投射神经元。我们进一步表明，即使是最小的选择性Nav1.1删除，使用PV-Cre，足以引起小鼠自发性癫痫发作和共济失调。总的来说，我们的研究结果表明，PV抑制性神经元的功能障碍与Nav1.1单倍不足有助于Dravet综合征的癫痫病理，并首次表明，Nav1.1单倍不足兴奋性神经元有改善作用的病理。
Dravet syndrome is a severe epileptic encephalopathy mainly caused by heterozygous mutations in the SCN1A gene encoding a voltage-gated sodium channel Nav1.1. We previously reported dense localization of Nav1.1 in parvalbumin (PV)-positive inhibitory interneurons in mice and abnormal firing of those neurons in Nav1.1-deficient mice. In the present study, we investigated the physiologic consequence of selective Nav1.1 deletion in mouse global inhibitory neurons, forebrain excitatory neurons or PV cells, using vesicular GABA transporter (VGAT)-Cre, empty spiracles homolog 1 (Emx1)-Cre or PV-Cre recombinase drivers. We show that selective Nav1.1 deletion using VGAT-Cre causes epileptic seizures and premature death that are unexpectedly more severe than those observed in constitutive Nav1.1-deficient mice. Nav1.1 deletion using Emx1-Cre does not cause any noticeable abnormalities in mice; however, the severe lethality observed with VGAT-Cre-driven Nav1.1 deletion is rescued by additional Nav1.1 deletion using Emx1-Cre. In addition to predominant expression in PV interneurons, we detected Nav1.1 in subpopulations of excitatory neurons, including entorhino-hippocampal projection neurons, a subpopulation of neocortical layer V excitatory neurons, and thalamo-cortical projection neurons. We further show that even minimal selective Nav1.1 deletion, using PV-Cre, is sufficient to cause spontaneous epileptic seizures and ataxia in mice. Overall, our results indicate that functional impairment of PV inhibitory neurons with Nav1.1 haploinsufficiency contributes to the epileptic pathology of Dravet syndrome, and show for the first time that Nav1.1 haploinsufficiency in excitatory neurons has an ameliorating effect on the pathology.
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影响因子：
16.2
作者：
Atallah BV;Bruns W;Carandini M;Scanziani M
通讯作者：
Scanziani M
影响因子：
64.8
作者：
Iwasato, T;Datwani, A;Itohara, S
通讯作者：
Itohara, S
影响因子：
9.8
作者：
通讯作者：
--
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。
影响因子：
6.1
作者：
Dutton SB;Makinson CD;Papale LA;Shankar A;Balakrishnan B;Nakazawa K;Escayg A
通讯作者：
Escayg A
影响因子：
3.7
作者：
Chan, CH;Godinho, LN;Parnavelas, JG
通讯作者：
Parnavelas, JG