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

γ-氨基丁酸（GABA）是哺乳动物中枢神经系统中主要的抑制性神经递质，由谷氨酸脱羧酶（GAD）的两种亚型GAD 65和GAD 67合成。我们通过同源重组法制备了GAD缺陷小鼠，并对其脑组织进行了分析以进一步阐明GABA的作用，结果表明GAD 67缺陷小鼠的胎儿和新生儿脑中GABA含量降至7%，而GAD 65缺陷小鼠的成年脑中GABA含量降至50-70%，表明GAD 67在胎儿期和GAD 65在出生后成熟期的重要性。这两种亚型的缺失并没有引起任何严重的脑结构缺陷。这一发现不支持目前的假设，GABA是至关重要的神经组织发生。GAD 67缺陷小鼠出现腭裂和呼吸神经网络活动异常。成年GAD 65缺陷小鼠在所有情绪行为测试中均表现出异常，提示更高的焦虑和异常的恐惧反应。膜片钳记录的突触活动在切片制备显示，自发抑制性传输减少，而兴奋性传输增强GAD 65缺陷的杏仁核。

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.