Hippocampal knock down of NMDA receptor induces deficit of PPI

海马 NMDA 受体敲低诱导 PPI 缺陷

• 批准号: 13671031
• 负责人: SUZUKI Eiji
• 金额: $ 1.86万
• 依托单位: Kitasato University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671031/
• 关键词: NMDA receptor; knock down; learning; nitric oxide; behavior; PPI

The present experiment conformed to the Guidelines on the ethical use of laboratory animals of Kitasato University. Male Wistar rats were used. The NR1 hippocampal knockdown was performed by single injection of NR1 antisense-HVJ-liposome complex into the bilateral hippocampus of rats. The sustained downregulation of expression of NR1 by NR1-antisense was confirmed by western blot analysis. Western blot analysis demonstrated that the NR1-antisense treatment provided specifically the downregulation (about 30%) of NR1 expression in the hippocampus for more than a week. Firstly, it was shown that disruption of pre-pulse inhibition (PPI) was produced in the rats with antisense-induced hippocampal knockdown of NMDA receptor NR1 subunit (NR1). Next, we examined whether this disruption of PPI in NR1 knockdown rats was recovered by dopamine receptor antagonist haloperidol (HPD), to clarify the relation between glutamate dysfunction and dopamine hyperfunction. On the PPI test, application of moderate or high dose of HPD induced recovery from defective PPI in the rats with NR1 knockdown by antisense.

本实验符合北里大学实验动物伦理使用指导原则。使用雄性Wistar大鼠。通过将NR 1反义核酸-HVJ-脂质体复合物单次注射到大鼠双侧海马中来进行NR 1海马敲低。Western blot分析证实NR 1反义核酸可持续下调NR 1的表达。Western blot分析表明，NR 1反义处理提供了特异性的下调（约30%）的NR 1在海马中的表达超过一周。首先，在反义诱导的海马NMDA受体NR 1亚单位（NR 1）敲低的大鼠中，前脉冲抑制（PPI）被破坏。接下来，我们研究了多巴胺受体拮抗剂氟哌啶醇（HPD）是否能恢复NR 1敲低大鼠PPI的这种中断，以澄清谷氨酸功能障碍和多巴胺功能亢进之间的关系。在PPI试验中，应用中等或高剂量的HPD可诱导NR 1反义基因敲除大鼠PPI缺陷的恢复。

项目成果

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Ken Inada, Jun Ishigooka, Takeshi Anzai, Eiji Suzuki, Hitoshi Miyaoka, Makoto Saji: "Antisense hippocampal knockdown of NMDA-NR1 by HVJ-liposome vector induces deficit of prepulse inhibition but not of spatial memory"Neuroscience Research. (in press).

Ken Inada、Jun Ishigooka、Takeshi Anzai、Eiji Suzuki、Hitoshi Miyaoka、Makoto Saji：“HVJ 脂质体载体对 NMDA-NR1 的反义海马敲低会导致前脉冲抑制缺陷，但不会导致空间记忆缺陷”神经科学研究。

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Eiji Suzuki., Toshio Nakaki., Futoshi Shintani., Shigenobu Kanba., Hitoshi Miyaoka.: "Antipsychotic, Antidepressant, Anxiolytic, and Anticonvulsant Drugs Induce Type II Nitric Oxide Synthase mRNA in Rat Brain. rs"Neuroscience Lette. 333(3). 217-219 (2002)

Eiji Suzuki.、Toshio Nakaki.、Futoshi Shintani.、Shigenobu Kanba.、Hitoshi Miyaoka.：“抗精神病药、抗抑郁药、抗焦虑药和抗惊厥药在大鼠大脑中诱导 II 型一氧化氮合酶 mRNA。rs”神经科学快报。

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