Mechanism for hippocampal neuron damage following intra-amygdaloid kainic acid-induced limbic seizures

杏仁内红藻氨酸诱导边缘癫痫发作后海马神经元损伤的机制

• 批准号: 09671424
• 负责人: SAJI Makoto
• 金额: $ 1.66万
• 依托单位: Kitasato University (1998)Tottori University (1997)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09671424/
• 关键词: temporallobe epilepsy; hippocampal pyramidal cell; neuron death; antisense DNA; synapsin I; hypothalamo-hippocampal afferent; kainic acid; 神経細胞障害; 上乳頭核-海馬系; ゲーティング機構; 海馬内情報伝搬

It has been reported that information flow in the hippocampus was modulated by afferent inputs from the supramammillary nucleus (SuM) of the hypothalamus. However, it is still unknown how this hypothalamo-hippocampal afferent regulates the signal flow in the hippocampus and whether generation of seizure activities in the temporal lobe epilepsy and the subsequent neuron damage in the hippocampus can be controlled by modulation of this afferent inputs. In the present study, 1) we demonstrated duringthe first term of project that there exists a gating mechanism at the dentate gyrus controlled by the hypothalamic afferent inputs which acts as a gate for the signal flow into the hippocampus in the manner of on/off switch, and in the second term of project 2) we tested using rat model of temporal lobe epilepsy induced by intraamygdala injection of kainic acid (KA) whether the sustained enhancement or sustained interruption of the hypothalamic afferent inputs modulates (ameliorates or deterio … More rates) the hippocampal neuron damage following the repetitive limbic seizures induced by intra-amygdala KA injection due to regulation of the gating mechanism. To enhance the hypothalamic afferent inputs during the long period (1-2 weeks), we used the cationic HVJ-liposome mediated gene transfer method for focal introduction of antisense oligodeoxynucleotides (ODNs) to synapsin I, regulatory protein for transmitter release, into the SuM of the hypothalamus which resulted in chronically enhanced efficacy of transmitter release in synaptic terminals of antisense-transfered hypothalamic neurons. Three-4 days after the antisense ODNs injection to the SuM, the rat received 0.4 mug/200 nl kainic acid into the ipsilateral amygdala which induced the class 5 limbic seizures, and subsequantly lead hippocampal neuron damage. As a results, the sustained enhancement of the hypothalamic afferent produced by the antisense ODNs injection to the SuM altered the hippocampal neuron damage from moderate damage of CAl neurons to severe damage of CA3 neurons. From the finding that the antisense ODNs treatment resulted in deterioration of hippocampal neuron damage following KA-induced limbic seizures, we concluded that the sustained enhancement of the hypothalamic afferent inputs intensified the limbic seizure activities in the hippocampus probably due to activation of the gate mechanism at the dentate gyrus and subsequently enhanced the process of glutamate excitotoxicity in the CA3 pyramidal neurons. Less

已有研究表明，下丘脑乳头体上核（SuM）的传入信息对海马内的信息流具有调制作用。然而，它仍然是未知的下丘脑-海马传入如何调节海马中的信号流，以及是否可以通过调制这种传入输入来控制颞叶癫痫中的癫痫发作活动的产生和随后的海马中的神经元损伤。在本研究中，1）我们在第一个学期的研究中证实了在下丘脑的传入输入控制下，齿状回存在一个门控机制，它以开关的方式作为信号流入海马的门，在项目2）的第二阶段，我们采用杏仁核内注射海人酸（KA）诱导的颞叶癫痫大鼠模型进行实验持续增强或持续中断下丘脑传入输入是否调节（改善或抑制）了下丘脑的神经功能， ...更多信息 杏仁核内注射KA诱导的边缘系统反复发作后，海马神经元的损伤由于门控机制的调节。为增强下丘脑长时间（1-2周）的传入，我们采用阳离子HVJ-脂质体介导的基因转移方法，将突触素Ⅰ（synapsin I）反义寡核苷酸（ODNs）导入下丘脑SuM，使反义寡核苷酸转染的下丘脑神经元突触终末的递质释放效应持续增强。在SuM注射反义ODNs后3 -4天，大鼠同侧杏仁核注射0.4 μ g/200 nl红藻氨酸，诱发5级边缘系统癫痫发作，并严重导致海马神经元损伤。结果表明，SuM区注射反义ODNs后，下丘脑传入神经持续增强，海马神经元损伤由CA 1区的中度损伤变为CA 3区的重度损伤。从发现反义ODNs治疗导致KA诱导的边缘癫痫发作后海马神经元损伤的恶化，我们得出结论，下丘脑传入输入的持续增强可能是由于激活齿状回的门控机制，从而增强了CA 3锥体神经元的谷氨酸兴奋毒性过程，从而增强了海马边缘癫痫发作活动。少

项目成果

Iwakuma, M.et al.: "Deterioration in the ischemic damage of hippocampal CA1 neurons by intraventricular administration of antisense DNA against synapsin I" Neurosci. Res.Suppl.22. 128 (1998)

Iwakuma, M.et al.：“通过脑室内注射针对突触蛋白 I 的反义 DNA 可改善海马 CA1 神经元的缺血性损伤” Neurosci。

Saji,M.et al..: "Modulation of propagation of neuroal activities in the hippocampal circuit by the supramammillo-hippocampal affrent pathway" Soc.Neurosci.Abst.23. 9751 (1997)

Saji,M.等人：“通过上乳头-海马传入通路调节海马回路中神经活动的传播”Soc.Neurosci.Abst.23。