Kobayashi Shizuka, Ohno Kousaku, Iwakuma Miwa, Kaneda Yasufumi, Saji Makoto
Department of Physiology, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa 228-8555, Japan.
Neurosci Res. 2002 Dec;44(4):455-65. doi: 10.1016/s0168-0102(02)00172-4.
We have previously demonstrated that an acute pharmacological interruption of the afferent inputs from the hypothalamus to the hippocampus resulted in the blockade of the genesis and spread of intra-amygdala kainate-induced seizure activity in the hippocampus. This finding suggests that a sustained interruption of the hypothalamic stimulative influences may completely prevent amygdaloid seizure-induced hippocampal neuron damage. To test this assumption, we delivered antisense oligodeoxynucleotides (ODNs) against synaptotagmin I, a regulatory protein of the transmitter release machinery, into the hypothalamus by using a Hemagglutinating virus of Japan (HVJ)-liposome-mediated gene transfer technique. Four days prior to the induction of status epilepticus by intra-amygdala injection of kainate, the synaptotagmin I antisense was injected into the supramammillary nucleus (SuM) of the hypothalamus to chronically suppress the stimulative influences to the hippocampus via the reduction of transmitter release. The synaptotagmin I hypothalamic knockdown resulted in the almost complete prevention of seizure-induced damage of hippocampal neurons but not of entorhinal neurons following the kainate-induced amygdaloid seizures. This result suggests that the hypothalamic stimulative influences to the hippocampus have a major contribution to the amygdaloid seizure-induced hippocampal sclerosis, probably via disinhibition mechanism.
我们之前已经证明，从下丘脑到海马体的传入输入的急性药理学阻断会导致杏仁核内海人酸诱导的癫痫活动在海马体中的发生和传播受到阻断。这一发现表明，下丘脑刺激影响的持续阻断可能会完全防止杏仁核癫痫诱导的海马体神经元损伤。为了验证这一假设，我们通过使用日本血凝病毒（HVJ）-脂质体介导的基因转移技术，将针对突触结合蛋白I（一种递质释放机制的调节蛋白）的反义寡脱氧核苷酸（ODN）导入下丘脑。在通过杏仁核内注射海人酸诱导癫痫持续状态的四天前，将突触结合蛋白I反义寡核苷酸注射到下丘脑的乳头体上核（SuM），以通过减少递质释放来长期抑制对海马体的刺激影响。突触结合蛋白I在下丘脑的敲低导致在海人酸诱导的杏仁核癫痫发作后，几乎完全防止了癫痫诱导的海马体神经元损伤，但对内嗅神经元没有作用。这一结果表明，下丘脑对海马体的刺激影响可能主要通过去抑制机制，对杏仁核癫痫诱导的海马体硬化起主要作用。
