Roles of GABA in the neural structure and function investigated in GAD-deficient mice.

GABA 在 GAD 缺陷小鼠神经结构和功能中的作用研究。

• 批准号: 10480229
• 负责人: OBATA Kunihiko
• 金额: $ 6.85万
• 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: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10480229/
• 关键词: GABA; glutamtic acid decarboxylase; gene targeting; mice; cleft palate; emotional behavior; amygdala; 情動; けいれん; ガンマ・アミノ酪酸; マウス; 神経発生

γ-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the mammalian central nervous system and synthesized by two isoforms of glutamic acid decarboxylase (GAD), GAD65 and GAD67. We produced GAD-deficient mice by homologous recombination and analyzed their brain for further elucidation of the roles of GABA.Brain GABA contents were reduced to 7% in the fetal and newborn GAD67-deficient mice and to 50-70% in the adult GAD65-deficient mice, indicating the importance of GAD67 at the fetal stage and GAD65 at postnatal maturation. Deletion of both isoforms did not induce any serious defects in brain structure. This finding does not support a current hypothesis that GABA is crucial for the neural histogenesis. GAD67-deficient mice showed cleft palate and abnormal activity of respiratory neural network. Adult GAD65-deficient mice showed the abnormality in every emotional behavior test, suggesting higher anxiety and abnormal fear response. Patch-clamp recording of synaptic activities in slice preparation revealed that spontaneous inhibitory transmission was reduced while the excitatory transmission was enhanced in the GAD65-deficient amygdala.

γ-氨基丁酸（GABA）是哺乳动物中枢神经系统中一种主要的抑制性神经递质，由谷氨酸脱羧酶（GAD）的GAD65和GAD67两种亚型合成。为了进一步阐明GABA的作用，我们采用同源重组的方法制备了GABA缺陷小鼠，并对其大脑进行了分析。胎儿和新生儿GAD67缺陷小鼠的脑GABA含量降低至7%，成年GAD65缺陷小鼠的脑GABA含量降低至50-70%，表明GAD67在胎儿期和出生后成熟时的重要性。这两种同工异构体的缺失没有引起大脑结构的任何严重缺陷。这一发现不支持目前关于GABA对神经组织发生至关重要的假设。gad67缺失小鼠出现腭裂和呼吸神经网络活动异常。成年gad65缺失小鼠在各项情绪行为测试中均出现异常，提示焦虑和恐惧反应异常。膜片钳记录的突触活动显示，在gad65缺失的杏仁核中，自发抑制性传递减少，兴奋性传递增强。

项目成果

Ding R.G., Asada H.& Obata K.: "Changes in extracellular glutamate and GABA levels in the hippocampal CA_3 and CA_1 areas and the induction of glutamic acid decarboxylase-67 in dentate granule cells of rats treated with kainic acid."Brain Res.. 800-1. 105

丁 R.G.，浅田 H.

Ji, F.Y., Kanbara, N. and Obata, K.: "GABA and histogenesis in fetal and neonatal mouse brain lacking both the isoforms of glutamic acid decarboxylase"Neuroscience Research. 33-3. 187-194 (1999)

Ji, F.Y.、Kanbara, N. 和 Obata, K.：“缺乏谷氨酸脱羧酶同工型的胎儿和新生小鼠大脑中的 GABA 和组织发生”神经科学研究。

Makinae K. et al.: "Structure of the mouse glutamate decarboxylase 65 gene and its promoter : Preferentia1 expression of its promoter in the GABAergic neurons of transgenic mice."J.Neurochem.. 75・4. 1429-1437 (2000)

Makinae K.等人：“小鼠谷氨酸脱羧酶65基因及其启动子的结构：其启动子在转基因小鼠的GABA能神经元中的优先表达”。J.Neurochem.. 75・4（2000）。

小幡邦彦: "GABAとてんかん"神経研究の進歩. 44-1. 5-12 (2000)

Kunihiko Obata：“GABA 和癫痫”神经学研究进展 44-1（2000）。

Obata, K., Asada, H. and Maruyama, K.: "Frontiers of Neural Development (Uyemura K. ed.)"Springer-Verlag, Tokyo. 544 (1999)

Obata, K.、Asada, H. 和 Maruyama, K.：“神经发育的前沿（Uyemura K. ed.）”Springer-Verlag，东京。