Strain- and age-dependent hippocampal neuron sodium currents correlate with epilepsy severity in Dravet syndrome mice.
Strain- and age-dependent hippocampal neuron sodium currents correlate with epilepsy severity in Dravet syndrome mice.
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DOI：
10.1016/j.nbd.2014.01.006
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发表时间：
2014-05
影响因子：
6.1
通讯作者：
Kearney JA
中科院分区：
文献类型：
--
作者：
Mistry AM;Thompson CH;Miller AR;Vanoye CG;George AL Jr;Kearney JA
杂合性功能丧失的SCN1A突变导致Drave氏综合征，这是一种婴儿期的癫痫脑病，表现出不同的临床严重性。我们利用杂合子Scn1a基因敲除(Scn1a+/−)的Drave氏综合征小鼠模型来研究表型变异的基础。这些动物表现出紧张依赖的癫痫发作严重程度和存活率。129S6/SvEvTac品系(129S6/SvEvTac)的Scn1a+/−小鼠与C57BL/6J品系(F1，Scn1a+/−)的Scn1a+/−小鼠相比，没有明显的表型和正常存活，后者有严重的癫痫和过早死亡。我们测试了海马神经元钠电流(INA)密度的菌株差异导致这些不同表型的假设。对出生后21~24天(P21~24)的急性分离的海马神经元进行全细胞电压钳记录，记录Scn1a+/−或F1。Scn1a+/−小鼠和野生型仔鼠。F1Scn1a+/−小鼠GABA能中间神经元INa密度低于野生型窝鼠，而12 9品系Scn1a+/−小鼠GABA能中间神经元INa密度与野生型对照无差异。相反，129Scn1a+/−和F1Scn1a+/−小鼠锥体神经元的INa密度均升高，并与这些神经元更频繁的自发动作电位放电以及F1Scn1a+/−神经元更持久的放电有关。我们还观察到野生型和Scn1a+/−动物之间锥体神经元INA密度的年龄差异。我们认为保存在GABA能中间神经元的INA密度有助于129，Scn1a+/−小鼠较温和的表型。此外，在F1Scn1a+/−小鼠中，P21-24处兴奋性锥体神经元内INa浓度的升高与年龄相关的致死性开始相关。我们的发现说明了海马神经元的差异，这可能是Dravet综合征小鼠模型中依赖应变和年龄的表型严重程度的基础，并强调了锥体神经元的兴奋性的贡献。
Heterozygous loss-of-function SCN1A mutations cause Dravet syndrome, an epileptic encephalopathy of infancy that exhibits variable clinical severity. We utilized a heterozygous Scn1a knockout (Scn1a+/−) mouse model of Dravet syndrome to investigate the basis for phenotype variability. These animals exhibit strain-dependent seizure severity and survival. Scn1a+/− mice on strain 129S6/SvEvTac (129.Scn1a+/−) have no overt phenotype and normal survival compared with Scn1a+/− mice bred to C57BL/6J (F1.Scn1a+/−) that have severe epilepsy and premature lethality. We tested the hypothesis that strain differences in sodium current (INa) density in hippocampal neurons contribute to these divergent phenotypes. Whole-cell voltage-clamp recording was performed on acutely-dissociated hippocampal neurons from postnatal day 21–24 (P21–24) 129.Scn1a+/− or F1.Scn1a+/− mice and wild-type littermates. INa density was lower in GABAergic interneurons from F1.Scn1a+/− mice compared to wild-type littermates, while on the 129 strain there was no difference in GABAergic interneuron INa between 129.Scn1a+/− mice and wild-type littermate controls. By contrast, INa density was elevated in pyramidal neurons from both 129.Scn1a+/− and F1.Scn1a+/− mice, and was correlated with more frequent spontaneous action potential firing in these neurons, as well as more sustained firing in F1.Scn1a+/− neurons. We also observed age-dependent differences in pyramidal neuron INa density between wild-type and Scn1a+/− animals. We conclude that preserved INa density in GABAergic interneurons contributes to the milder phenotype of 129.Scn1a+/− mice. Furthermore, elevated INa density in excitatory pyramidal neurons at P21–24 correlates with age-dependent onset of lethality in F1.Scn1a+/− mice. Our findings illustrate differences in hippocampal neurons that may underlie strain- and age-dependent phenotype severity in a Dravet syndrome mouse model, and emphasize a contribution of pyramidal neuron excitability.
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影响因子：
3.5
作者：
Ogiwara I;Iwasato T;Miyamoto H;Iwata R;Yamagata T;Mazaki E;Yanagawa Y;Tamamaki N;Hensch TK;Itohara S;Yamakawa K
通讯作者：
Yamakawa K
影响因子：
1.7
作者：
Kimura, K;Sugawara, T;Segawa, M
通讯作者：
Segawa, M
影响因子：
16.2
作者：
WESTENBROEK, RE;MERRICK, DK;CATTERALL, WA
通讯作者：
CATTERALL, WA
影响因子：
3.5
作者：
Martin, Melinda S.;Tang, Bin;Escayg, Andrew
通讯作者：
Escayg, Andrew
影响因子：
5.6
作者：
Bechi, Giulia;Scalmani, Paolo;Mantegazza, Massimo
通讯作者：
Mantegazza, Massimo