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Roles of GABA in the development of the nervous system : analysis of GAD-deficient mice

GABA 在神经系统发育中的作用：GAD 缺陷小鼠的分析

基本信息

批准号：
13480269
负责人：
OBATA Kunihiko
金额：
$ 6.08万
依托单位：
Okazaki National Research Institutes
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
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

项目摘要

γ-Aminobutyric acid (GABA) is synthesized from glutamate by two isoforms of glutamic acid decarboxylase (GAD), GAD65 and GAD67. In order to further elucidate the roles of GABA in the developing and mature brain, we have generated GAD gene-knockout mice and analyzed their phenotypes. While GAD65 is developed postnatally and its deficiency results in seizure and abnormal emotional behavior, expression of GAD67 starts simultaneously with differentiation of GABAergic neuron at an early embryonic stage. Development of GABAergic neurons was studied in the superior colliculus (SC) of the GAD67+/- and GFP+/- mice. Although the SC is layered structure as the neocortex, its GABAergic neurons were originated together with other neurons from the nearby ventricular zone. Before GABAergic neurons were differentiated in the SC, abundant GABAergic fibers were transiently present on the surface. They originated probably outside of SC and crossed the midline, suggesting their developmental roles. GAD67-/- mice contained less than 10% of GABA compared with the wild type but did not show any serious defect in their brain structure. Neural function of GAD67 knockout mice did not survive after birth because of cleft plate and their neural function could not studied in adult animals. When the brainstem isolated from the embryo or newborn was studied electrophyiologically, respiratory rhythm and inhibitory synaptic currents in respiratory neurons were greatly impaired.

γ-氨基丁酸（GABA）是由谷氨酸脱羧酶（GAD）的GAD65和GAD67两个亚型合成的。为了进一步阐明GABA在发育和成熟大脑中的作用，我们培育了GAD基因敲除小鼠，并分析了它们的表型。GAD65在出生后发育，其缺乏导致癫痫发作和异常情绪行为，而GAD67的表达在胚胎早期与gaba能神经元的分化同时开始。研究了GAD67+/-和GFP+/-小鼠上丘gaba能神经元的发育。虽然SC是层状结构的新皮层，但其gaba能神经元与邻近心室区的其他神经元一起起源。在SC内gabaergy神经元分化前，表面短暂存在丰富的gabaergy纤维。它们可能起源于SC外并越过中线，这表明它们在发育中起着重要作用。与野生型相比，GAD67-/-小鼠的GABA含量低于10%，但其大脑结构未出现任何严重缺陷。GAD67基因敲除小鼠出生后由于板裂导致神经功能缺失，无法在成年动物中进行神经功能研究。对胚胎或新生儿分离的脑干进行电生理研究，发现呼吸神经元的呼吸节律和抑制性突触电流明显受损。