Scn1a missense mutation causes limbic hyperexcitability and vulnerability to experimental febrile seizures

被引:28
作者
Ohno, Yukihiro [1 ]
Ishihara, Shizuka [1 ]
Mashimo, Tomoji [2 ]
Sofue, Nobumasa [1 ]
Shimizu, Said [1 ]
Imaoku, Takuji [1 ]
Tsurumi, Toshiko [2 ]
Sasa, Masashi [3 ]
Serikawa, Tadao [2 ]
机构
[1] Osaka Univ Pharmaceut Sci, Pharmacol Lab, Osaka 5691094, Japan
[2] Kyoto Univ, Grad Sch Med, Inst Lab Anim, Kyoto 6068501, Japan
[3] Nagisa Clin, Osaka 5731183, Japan
关键词
Febrile seizure; Na(v)1.1 channel; Scn1a; Missense mutation; Rat model; SEVERE MYOCLONIC EPILEPSY; GENERALIZED EPILEPSY; MOUSE MODEL; SODIUM-CHANNELS; PLUS; INTERNEURONS; INJURY; AGE;
D O I
10.1016/j.nbd.2010.09.013
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Mutations of the voltage-gated sodium (Nag) channel subunit SCN1A have been implicated in the pathogenesis of human febrile seizures including generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy in infancy (SMEI). Hyperthermia-induced seizure-susceptible (Hiss) rats are the novel rat model carrying a missense mutation (N1417H) of Scn1a, which is located in the third pore-forming region of the Na(v)1.1 channel. Here, we conducted behavioral and neurochemical studies to clarify the functional relevance of the Scn1a mutation in vivo and the mechanism underlying the vulnerability to hyperthermic seizures. Hiss rats showed markedly high susceptibility to hyperthermic seizures (mainly generalized clonic seizures) which were synchronously associated with paroxysmal epileptiform discharges. Immunohistochemical analysis of brain Fos expression revealed that hyperthermic seizures induced a widespread elevation of Fos-immunoreactivity in the cerebral cortices including the motor area, piriform, and insular cortex. In the subcortical regions, hyperthermic seizures enhanced Fos expression region-specifically in the limbic and paralimbic regions (e.g., hippocampus, amygdala, and perirhinal-entorhinal cortex) without affecting other brain regions (e.g., basal ganglia, diencephalon, and lower brainstem), suggesting a primary involvement of limbic system in the induction of hyperthermic seizures. In addition, Hiss rats showed a significantly lower threshold than the control animals in inducing epileptiform discharges in response to local stimulation of the hippocampus (hippocampal afterdischarges). Furthermore, hyperthermic seizures in Hiss rats were significantly alleviated by the antiepileptic drugs, diazepam and sodium valproate, while phenytoin or ethosuximide were ineffective. The present findings support the notion that Hiss rats are useful as a novel rat model of febrile seizures and suggest that hyperexcitability of limbic neurons associated with Scn1a missense mutation plays a crucial role in the pathogenesis of febrile seizures. (C) 2010 Elsevier Inc. All rights reserved.
引用
收藏
页码:261 / 269
页数:9
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