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Epilepsy, Headache, Vertigo

開催日 2014/9/11
時間 16:00 - 17:00
会場 Poster / Exhibition(Event Hall B)

シナプス小胞蛋白SV2A変異 (Sv2aL174Q) ラットにおけるキンドリング形成の促進
Enhanced kindling development in synaptic vesicle protein 2A-mutant (Sv2aL174Q) rats

  • P1-348
  • 徳留 健太郎 / Kentaro Tokudome:1 奥村 貴裕 / Takahiro Okumura:1 真下 知士 / Tomoji Mashimo:2 國澤 直史 / Naofumi Kunisawa:1 清水 佐紀 / Saki Shimizu:1 寺田 亮 / Ryo Terada:1 芹川 忠夫 / Tadao Serikawa:1,2 笹 征史 / Masashi Sasa:1,3 大野 行弘 / Yukihiro Ohno:1 
  • 1:大阪薬大・薬・薬品作用解析 / Lab. Pharmacol., Osaka Univ. Pharma. Sci, Osaka, Japan 2:京都大学大学院医学研究科動物実験施設 / Inst. Lab. Animals, Kyoto Univ. Sch. Med, Kyoto, Japan 3:渚クリニック / Nagisa Clinic, Osaka, Japan 

Synaptic vesicle protein 2A (SV2A) is the prototype protein specifically identified in the synaptic vesicles and is now known as the action site of antiepileptics (i.e., levetiracetam derivatives). In addition, SV2A knockout mice evoke severe convulsions and early death, implying that SV2A is implicated in the pathogenesis of epileptic disorders. To investigate the role of SV2A in modulating kindling epileptogenesis, we conducted behavioral and electrophysiological studies using novel Sv2aL174Q mutant rats generated by ENU mutagenesis (SV2A-mutant rats). SV2A-mutant rat showed a high susceptibility to pentylenetetrazole (PTZ)-evoked seizure, but not to pilocarpine- or 4-aminopyridine-evoked seizure. In the kindling study with low dose (30 mg/kg/day for 9 days) of PTZ, SV2A-mutant rats were more sensitive to PTZ-evoked kindling than control (F344) animals, yielding higher seizure severity scores and incidence rate. In addition, kindling responses of SV2A-mutant rats to electrical stimulation of the amygdala were also significantly facilitated although the threshold for seizure discharges upon the acute amygdala stimulation was unaltered. In in vitro electrophysiological study using hippocampus slices, population spike (PS) amplitude of CA1 field elicited by stimulation of the Schaffer collateral/commissural fibers was remarkably increased in SV2A-mutant rats as compared to control animals while the stimulus threshold for PS generation per se was unaltered. Furthermore, the paired-pulse (P-P)-induced facilitation of PS, which is known to be mediated by NMDA receptors, was unaffected by the SV2A mutation. These results show that dysfunction of SV2A by the Sv2aL174Q mutation significantly increases neural excitability in the limbic system and facilitates the kindling development, illustrating an inhibitory function of SV2A in controlling the kindling epileptogenesis.

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