Molecular genetic and experimental studies on abnormalities of glutamatergic transmission in schizophrenia

精神分裂症谷氨酸能传递异常的分子遗传学和实验研究

• 批准号: 11670936
• 负责人: SUZUKI Michio
• 金额: $ 2.24万
• 依托单位: TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670936/
• 关键词: glutamate; N-acetylated alpha-linked acidic dipeptidase (NAALADase); N-methyl-D-aspartate (NMDA) receptor; antisense oligodeoxynucleotide; dopamine D2 receptor; phencyclidine; social interaction; schizophrenia; 精神分裂病; 分子遺伝学; ノックダウン; in situ ハイブ

Following studies were undertaken to investigate the pathophysiology underlying abnormalities of glutamatergic transmission in schizophrenia. First, a molecular genetic abnormality in gene encoding N-acetylated alpha-linked acidic dipeptidase (NAALADase) was investigated in patients with schizophrenia. Second, experimental studies were performed using several possible animal models of schizophrenia. Rats administered with antisense oligonucleotide complementary to mRNA of NAALADase into the bilateral entorhinal cortex did not show changes in spontaneous locomotor activity or metamphetamine-induced locomotor activity. Intracerebroventricular administration to rats with antisense oligonucleotide complementary to mRNA of N-methyl-D aspartate (NMDA) R1 subunit induced a significant reduction in dopamine D2 receptor density in the substantia nigra using in vitro [3H] YM-09151-2 autoradiography as well as a significant increase in dopamine D2 mRNA in the striatum using northern blot analysis. In rats treated chronically with non-competitive NMDA antagonist, phencyclidine or MK-801, behaviors related social interaction were significantly decreased.

本研究旨在探讨精神分裂症患者神经递质传递异常的病理生理学基础。首先，研究了精神分裂症患者编码N-乙酰化α-连接酸性二肽酶（NAALADase）基因的分子遗传异常。其次，使用几种可能的精神分裂症动物模型进行实验研究。大鼠给予反义寡核苷酸互补的mRNA的NAALADase到双边内嗅皮层没有表现出自发运动活动或甲基苯丙胺诱导的运动活动的变化。使用体外[3 H] YM-09151-2放射自显影术，向大鼠脑室内给予与N-甲基-D天冬氨酸（NMDA）R1亚基mRNA互补的反义寡核苷酸，可诱导黑质多巴胺D2受体密度显著降低，使用北方印迹分析，可诱导纹状体多巴胺D2 mRNA显著增加。在非竞争性NMDA拮抗剂，苯环利定或MK-801长期治疗的大鼠，与社会互动相关的行为显着减少。

项目成果

Tajiri K, Emori K, Murata M, Tanaka K, Suzuki M, Uehara T, Sumiyoshi T, et al.: "Intracerebroventricular administration of NMDA-R1 antisense oligodeoxynucleotide significantly alters the activity of ventral tegmental area dopamine neurons."Synapse. 40. 27

Tajiri K、Emori K、Murata M、Tanaka K、Suzuki M、Uehara T、Sumiyoshi T 等人：“脑室内给予 NMDA-R1 反义寡脱氧核苷酸可显着改变腹侧被盖区多巴胺神经元的活性。”突触。

Kurachi M, Sumiyoshi T, ShibataR, SunY-J, Uehara T, Tanii Y, Suzuki M: "Changes in limbic dopamine metabolism following quinolinic acid lesions of the left entorhinal cortex in rats"Psychiatry and Clinical Neurosciences. 54. 83-89 (2000)

Kurachi M、Sumiyoshi T、ShibataR、SunY-J、Uehara T、Tanii Y、Suzuki M：“大鼠左内嗅皮层喹啉酸损伤后边缘多巴胺代谢的变化”精神病学和临床神经科学。

Tajiri K, Emori K, Murata M, Tanaka K, Suzuki M, Uehara T, Sumiyoshi T, et al.: "Intracerebroventricular administration of NMDA-R1 antisense oligodeoxynucleotide significantly alters the activity of ventral tegmental area dopamine neurons"Synapse. 40. 275

Tajiri K、Emori K、Murata M、Tanaka K、Suzuki M、Uehara T、Sumiyoshi T 等人：“脑室内给予 NMDA-R1 反义寡脱氧核苷酸可显着改变腹侧被盖区多巴胺神经元的活性”突触。

Tajiri K, Emori K, Murata M, Tanaka K, Suzuki M, Uehara T, Sumiyoshi T, Kurachi M, Ashby Jr CR: "The intracerebroventricular administration of NMDA-R1 antisense oligodeoxynucleotide significantly alters the activity of ventral tegmental area dopamine neur

Tajiri K、Emori K、Murata M、Tanaka K、Suzuki M、Uehara T、Sumiyoshi T、Kurachi M、Ashby Jr CR：“脑室内施用 NMDA-R1 反义寡脱氧核苷酸显着改变腹侧被盖区多巴胺神经元的活性

Kurachi M, Sumiyoshi T, Shibata R, Sun Y-J, Uehara T, Tanii Y, Suzuki M: "Changes in limbic dopamine metabolism following quinolinic acid lesions of the left entorhinal cortex in rats"Psychiatry and Clinical Neurosciences. 54. 83-89 (2000)

Kurachi M、Sumiyoshi T、Shibata R、Sun Y-J、Uehara T、Tanii Y、Suzuki M：“大鼠左内嗅皮层喹啉酸损伤后边缘多巴胺代谢的变化”精神病学和临床神经科学。