Early-life febrile seizures worsen adult phenotypes in Scn1a mutants.
Early-life febrile seizures worsen adult phenotypes in Scn1a mutants.
复制标题
DOI：
10.1016/j.expneurol.2017.03.026
复制
发表时间：
2017-07
影响因子：
5.3
通讯作者：
Escayg A
中科院分区：
文献类型：
--
作者：
Dutton SBB;Dutt K;Papale LA;Helmers S;Goldin AL;Escayg A
电压门控钠通道（VGSC）基因SCN 1A（编码Nav1.1通道）的突变导致许多癫痫疾病，包括遗传性癫痫伴热性惊厥+（GEFS+）和Dravet综合征（DS）。具有SCN 1A突变的患者经常经历长期的早期热性惊厥（FS），这增加了这些事件可能影响癫痫发生并导致更严重的成人表型的可能性。为了验证这一假设，我们将表达人SCN 1A GEFS+突变R1648 H的21-23日龄小鼠置于长期高温下，然后检查成年期的癫痫发作和行为表型。我们发现，早期生活FS导致较低的lavonto诱导癫痫发作，增加自发性癫痫发作的严重程度，多动，并在成年期的社会行为和识别记忆的损害。脑切片制剂的生物物理分析显示，沿着动作电位放电增加，CA 3锥体神经元癫痫样活动增加，为观察到的成人表型恶化提供了机制基础。这些发现表明了早期FS对疾病结局的长期负面影响。这对这一患者人群的临床管理具有重要意义，并强调了对可改善疾病进展的治疗干预的需求。
Mutations in the voltage-gated sodium channel (VGSC) gene SCN1A, encoding the Nav1.1 channel, are responsible for a number of epilepsy disorders including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (DS). Patients with SCN1A mutations often experience prolonged early-life febrile seizures (FSs), raising the possibility that these events may influence epileptogenesis and lead to more severe adult phenotypes. To test this hypothesis, we subjected 21-23-day-old mice expressing the human SCN1A GEFS+ mutation R1648H to prolonged hyperthermia, and then examined seizure and behavioral phenotypes during adulthood. We found that early-life FSs resulted in lower latencies to induced seizures, increased severity of spontaneous seizures, hyperactivity, and impairments in social behavior and recognition memory during adulthood. Biophysical analysis of brain slice preparations revealed an increase in epileptiform activity in CA3 pyramidal neurons along with increased action potential firing, providing a mechanistic basis for the observed worsening of adult phenotypes. These findings demonstrate the long-term negative impact of early-life FSs on disease outcomes. This has important implications for the clinical management of this patient population and highlights the need for therapeutic interventions that could ameliorate disease progression.
登录
查看更多内容
影响因子：
82.9
作者：
Chen, K;Baram, TZ;Soltesz, I
通讯作者：
Soltesz, I
影响因子：
5.3
作者：
Brewster, A;Bender, RA;Baram, TZ
通讯作者：
Baram, TZ
影响因子：
6.1
作者：
Abraham, Jayne;Fox, Patrick D.;Condello, Carlo;Bartolini, Alyssa;Koh, Sookyong
通讯作者：
Koh, Sookyong
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：
11.2
作者：
Chang, YC;Huang, AM;Huang, CC
通讯作者：
Huang, CC