Aldehyde dehydrogenase 1a1 mediates a GABA synthesis pathway in midbrain dopaminergic neurons.
Aldehyde dehydrogenase 1a1 mediates a GABA synthesis pathway in midbrain dopaminergic neurons.
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DOI：
10.1126/science.aac4690
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发表时间：
2015-10-02
期刊：
影响因子：
--
通讯作者：
Ding JB
中科院分区：
文献类型：
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作者：
Kim JI;Ganesan S;Luo SX;Wu YW;Park E;Huang EJ;Chen L;Ding JB
中脑多巴胺神经元是基底神经节回路的重要组成部分，在精细运动和奖励的控制中发挥着关键作用。最近，研究表明，主要的抑制性神经递质γ-氨基丁酸（GABA）是由多巴胺神经元共同释放的。在这里，我们表明多巴胺神经元中的 GABA 共释放不利用传统的 GABA 合成酶、谷氨酸脱羧酶 GAD65 和 GAD67。我们的实验揭示了由乙醛脱氢酶 1a1 (ALDH1a1) 介导的进化上保守的 GABA 合成途径。此外，在酗酒时，GABA 的共释放受到乙醇的调节，而 ALDH1a1 的减少会导致酒精消耗和偏好增加。这些发现为了解 GABA 共释放在中脑多巴胺神经元中的功能作用提供了见解，这对于基于奖励的行为和成瘾可能至关重要。
Midbrain dopamine neurons are an essential component of the basal ganglia circuitry, playing key roles in the control of fine movement and reward. Recently, it has been demonstrated that γ-aminobutyric acid (GABA), the chief inhibitory neurotransmitter, is co-released by dopamine neurons. Here we show that GABA corelease in dopamine neurons does not utilize the conventional GABA synthesizing enzymes, glutamate decarboxylases GAD65 and GAD67. Our experiments reveal an evolutionarily conserved GABA synthesis pathway mediated by aldehyde dehydrogenase 1a1 (ALDH1a1). Moreover, GABA co-release is modulated by ethanol at binge drinking blood alcohol concentrations and diminished ALDH1a1 leads to enhanced alcohol consumption and preference. These findings provide insights into the functional role of GABA co-release in midbrain dopamine neurons, which may be essential for reward-based behavior and addiction.