Roles of GABA in neural development and plasticity : produciton and analysis of GABA-synthesizing enzyme (GAD) -deficient mice

GABA 在神经发育和可塑性中的作用：GABA 合成酶 (GAD) 缺陷小鼠的生产和分析

• 批准号: 08458263
• 负责人: OBATA Kunihiko
• 金额: $ 4.54万
• 依托单位: NATIONAL INSTITUTE FOR PHYSIOLOGICAL SCIENCES
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08458263/
• 关键词: GABA; glutamtic acid decarboxylase; gene targeting; mouse brain; cleft palate; γ・アミノ酪酸

In order to elucidate the roles of gamma-aminobutyric acid (GABA) in the development of the neural and non-neural tissues and in the various functions of each brain region, the genes encoding GABA-synthesizing enzyme, glutamic acid decarboxylase (GAD) in the mice were disrupted by gene targeting. GAD has two isoforms, GAD65 and GAD67, and expectedly their respective roles, so far unknown, would be clarified. GAD65-deficient mice could grow normally and did not show serious behavioral abnormailites. Their brain contained normal level of GABA and did not show histological abnormalities. On the other hand, GAD67-deficient mice were born as expected but died of severe cleft palate soon after birth. Their brain contained only 7% of GABA found in the wild-type brain in spite of their norman histoloy. These results have shown that GAD67 is an important isoform of GAD in the mouse brain. We are investigating on 1 involvement of GABA in development of palate and other non neural tissue and 2 production of GAD67-deficient mice rescued from cleft palate using inducible knockout technique. As GAD65 knockout mice showed moderate changes in responsiveness to convulsant and antipsychotic drugs, we are now analyzing the functions of the GAD65-deficient striatum, circadian system and other brain areas.

为了阐明γ-氨基丁酸(GABA)在神经和非神经组织发育中的作用，以及在各个脑区的不同功能中的作用，通过基因打靶的方法扰乱了小鼠GABA合成酶谷氨酸脱羧酶(GAD)的基因。GAD有两种亚型，GAD65和GAD67，预计它们各自的作用将被澄清，目前尚不清楚。GAD65基因缺陷小鼠可正常生长，未出现严重的行为异常。他们的大脑含有正常水平的GABA，并且没有表现出组织学上的异常。另一方面，GAD67基因缺陷的小鼠如预期的那样出生，但出生后不久就死于严重的腭裂。尽管他们有诺曼人的组织学特征，但他们的大脑中只含有野生型大脑中7%的GABA。这些结果表明，GAD67是小鼠脑中GAD的一个重要亚型。我们正在研究1 GABA在腭部和其他非神经组织发育中的作用以及2利用诱导性基因敲除技术从腭裂中拯救GAD67缺陷小鼠的产物。由于GAD65基因敲除小鼠对惊厥和抗精神病药物的反应性显示出适度的变化，我们现在正在分析GAD65缺陷的纹状体、昼夜节律系统和其他大脑区域的功能。

项目成果

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Sekino Y. 等人：“通过光学记录揭示大鼠海马切片中通过 CA2 的延迟信号传播”《神经生理学杂志》。

Hideo Asada et al.: "Mice lacking the 65 kDa isoform of glutamic acid decarcbxylase (GAD65) main tain normal levels of GAD67 and GABA in their brains but susceptible to seizures" Biochem.Biophysical Res.Communications. 229,3. 891-895 (1996)

Hideo Asada 等人：“缺乏 65 kDa 谷氨酸脱羧酶 (GAD65) 亚型的小鼠大脑中 GAD67 和 GABA 保持正常水平，但容易癫痫发作”Biochem.Biophysical Res.Communications。

Tomita T.et al.: "The presenilin 2 mutation (N141I) linked to familial Alzheimer's disease (Volga German families) increases the secretion of amyloid s protein ending at Abeta42 (43)." Proc Natl Acad Sci USA. 94. 2025-2030 (1997)

Tomita T.等人：“与家族性阿尔茨海默氏病（伏尔加德国家族）相关的早老素 2 突变 (N141I) 增加了以 Abeta42 结尾的淀粉样蛋白的分泌 (43)。”

Shinozaki K.et al.: "A novel brain gene, Norbin, induced by treatment of tetraethylammonium in rat Hippocampal slice and accompaned with neurite-outgrowth in Neuro 2a cells." Biochem Biophys Res Commun. 240. 766-771 (1997)

Shinozaki K.等人：“一种新的大脑基因 Norbin，是通过四乙铵处理大鼠海马切片诱导的，并伴随着 Neuro 2a 细胞中的神经突生长。”

Kunihiko Obata: "Excitatory and trophic action of GABA and related substances in newborn mice and organotypic cerebellar culture" Developmental Neuroscience. 19,1. 117-119 (1997)

Kunihiko Obata：“新生小鼠和器官型小脑培养中 GABA 和相关物质的兴奋和营养作用”发育神经科学。