乙醛脱氢酶1a1介导中脑多巴胺能神经元中的γ-氨基丁酸合成途径。
Aldehyde dehydrogenase 1a1 mediates a GABA synthesis pathway in midbrain dopaminergic neurons.
作者信息
Kim Jae-Ick, Ganesan Subhashree, Luo Sarah X, Wu Yu-Wei, Park Esther, Huang Eric J, Chen Lu, Ding Jun B
机构信息
Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA 94304, USA.
Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA. Neuroscience Graduate Program, University of California San Francisco, San Francisco, CA 94143, USA.
出版信息
Science. 2015 Oct 2;350(6256):102-6. doi: 10.1126/science.aac4690.
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 co-release in dopamine neurons does not use 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 (EtOH) at concentrations seen in blood alcohol after binge drinking, 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.
中脑多巴胺神经元是基底神经节回路的重要组成部分，在精细运动控制和奖赏中发挥关键作用。最近，有研究表明，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。在此，我们表明多巴胺神经元中GABA的共同释放并不使用传统的GABA合成酶，即谷氨酸脱羧酶GAD65和GAD67。我们的实验揭示了一种由醛脱氢酶1a1（ALDH1a1）介导的进化上保守的GABA合成途径。此外，在暴饮后血液酒精浓度下，GABA的共同释放受到乙醇（EtOH）的调节，而ALDH1a1的减少会导致酒精摄入量和偏好增加。这些发现为中脑多巴胺神经元中GABA共同释放的功能作用提供了见解，这可能对基于奖赏的行为和成瘾至关重要。
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