Neuroscience Discovery, Pfizer Research, Princeton, New Jersey 08543, and Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, United Kingdom.
J Neurosci. 2010 Feb 10;30(6):2017-24. doi: 10.1523/JNEUROSCI.5693-09.2010.
Endocannabinoids (eCBs) function as retrograde signaling molecules at synapses throughout the brain, regulate axonal growth and guidance during development, and drive adult neurogenesis. There remains a lack of genetic evidence as to the identity of the enzyme(s) responsible for the synthesis of eCBs in the brain. Diacylglycerol lipase-alpha (DAGLalpha) and -beta (DAGLbeta) synthesize 2-arachidonoyl-glycerol (2-AG), the most abundant eCB in the brain. However, their respective contribution to this and to eCB signaling has not been tested. In the present study, we show approximately 80% reductions in 2-AG levels in the brain and spinal cord in DAGLalpha(-/-) mice and a 50% reduction in the brain in DAGLbeta(-/-) mice. In contrast, DAGLbeta plays a more important role than DAGLalpha in regulating 2-AG levels in the liver, with a 90% reduction seen in DAGLbeta(-/-) mice. Levels of arachidonic acid decrease in parallel with 2-AG, suggesting that DAGL activity controls the steady-state levels of both lipids. In the hippocampus, the postsynaptic release of an eCB results in the transient suppression of GABA-mediated transmission at inhibitory synapses; we now show that this form of synaptic plasticity is completely lost in DAGLalpha(-/-) animals and relatively unaffected in DAGLbeta(-/-) animals. Finally, we show that the control of adult neurogenesis in the hippocampus and subventricular zone is compromised in the DAGLalpha(-/-) and/or DAGLbeta(-/-) mice. These findings provide the first evidence that DAGLalpha is the major biosynthetic enzyme for 2-AG in the nervous system and reveal an essential role for this enzyme in regulating retrograde synaptic plasticity and adult neurogenesis.
内源性大麻素（eCBs）作为大脑中突触的逆行信号分子发挥作用，在发育过程中调节轴突生长和导向，并驱动成年神经发生。目前仍然缺乏关于负责大脑中 eCB 合成的酶（s）的遗传证据。二酰基甘油脂肪酶-α（DAGLalpha）和-β（DAGLbeta）合成 2-花生四烯酰甘油（2-AG），这是大脑中最丰富的 eCB。然而，它们各自对这一点和对 eCB 信号转导的贡献尚未得到测试。在本研究中，我们发现 DAGLalpha（-/-）小鼠的大脑和脊髓中的 2-AG 水平降低了约 80%，而 DAGLbeta（-/-）小鼠的大脑中的 2-AG 水平降低了 50%。相比之下，DAGLbeta 在调节肝脏中的 2-AG 水平方面比 DAGLalpha 更重要，DAGLbeta（-/-）小鼠中观察到 90%的降低。花生四烯酸的水平与 2-AG 平行下降，这表明 DAGL 活性控制这两种脂质的稳态水平。在海马体中，eCB 的突触后释放导致抑制性突触中 GABA 介导的传递短暂抑制；我们现在表明，这种形式的突触可塑性在 DAGLalpha（-/-）动物中完全丧失，而在 DAGLbeta（-/-）动物中相对不受影响。最后，我们表明 DAGLalpha（-/-）和/或 DAGLbeta（-/-）小鼠的海马体和侧脑室下区的成年神经发生的控制受到损害。这些发现首次提供了证据表明 DAGLalpha 是神经系统中 2-AG 的主要生物合成酶，并揭示了该酶在调节逆行突触可塑性和成年神经发生中的重要作用。
