Postnatal development of a GABA deficit and disturbance of neural functions in mice lacking GAD65
Postnatal development of a GABA deficit and disturbance of neural functions in mice lacking GAD65
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DOI：
10.1016/s0006-8993(00)02206-x
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发表时间：
2000-05-19
期刊：
影响因子：
2.9
通讯作者：
Obata, K
中科院分区：
文献类型：
--
作者：
Stork, O;Ji, FY;Obata, K
谷氨酸脱羧酶（GAD 65）的65 kDa亚型被认为在中枢神经系统中对GABA合成起重要作用。使用GAD 65基因靶向破坏的小鼠（GAD 65（-/-）小鼠），我们研究了GAD 65对出生后发育和成年期不同脑区GABA合成的贡献。在GAD 65（+/+）小鼠的杏仁核、下丘脑和顶叶皮质中，在出生后发育期间观察到GABA水平的增加，在第一个ii-小鼠和出生后第二个月之间最显著。这种增加似乎依赖于GAD 65，因为在GAD 65（-/-）小鼠中未观察到GAD 65延迟2个月。成年GAD 65（-/-）小鼠表现出很大程度上异常的神经活动，频繁的阵发性放电和自发性癫痫发作，这可能是其GABA缺陷的结果。他们还显示增加焦虑样行为在光/暗回避测试和减少intermale侵略，以及减少强迫游泳诱导的不动性的抗抑郁剂样的行为变化的指示。成年GAD 65（-/-）小鼠未显示出行为障碍，但攻击行为减少，与GAD 65（-/-）小鼠相当。我们的结论是，GAD 65介导的GABA合成可能是至关重要的参与控制情绪行为和不可或缺的毛皮紧张性抑制，防止过度兴奋的发展成熟的中枢神经系统。攻击性和其他可能的社会行为可能特别容易通过GAD 65介导的GABA合成进行调节。(C)2000 Elsevier Science B. V.保留所有权利。
The 65-kDa isoform of glutamic acid decarboxylase (GAD65) is believed to play an essential role for GABA synthesis in the central nervous system. Using mice with targeted disruption of the GAD65 gene (GAD65(-/-) mice) we investigated the contribution of GAD65 to GABA synthesis in different brain areas during postnatal development and in adulthood. In the amygdala, hypothalamus and parietal cortex of GAD65(+/+) mice an increase of GABA levels was observed during postnatal development, most prominently between the first ii- mice and and second month after birth. This increase appeared to be dependent on GAD65, as it was delayed by 2 months in GAD65 was not observed in GAD65(-/-) mice. Likely as a consequence of their GABA deficit, adult GAD65(-/-) mice showed a largely abnormal neural activity with frequent paroxysmal discharges and spontaneous seizures. They furthermore displayed increased anxiety-like behaviour in a light/dark avoidance test and reduced intermale aggression, as well as a reduced forced-swimming-induced immobility indicative of an antidepressant-like behavioural change. Adult GAD65(-/-) mice did not show behavioural disturbances except for a reduced aggressive behaviour that was comparable to that in GAD65(-/-) mice. We conclude that GAD65-mediated GABA synthesis may be crucially involved in control of emotional behaviour and indispensable fur a tonic inhibition that prevents the development of hyperexcitability in the maturating central nervous system. Aggressive, and possibly other social behaviour may be especially prone to regulation through GAD65-mediated GABA synthesis. (C) 2000 Elsevier Science B.V. All rights reserved.