A cannabinoid link between mitochondria and memory
A cannabinoid link between mitochondria and memory
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DOI：
10.1038/nature20127
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发表时间：
2016-11-24
期刊：
影响因子：
64.8
通讯作者：
Marsicano, Giovanni
中科院分区：
文献类型：
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作者：
Hebert-Chatelain, Etienne;Desprez, Tifany;Marsicano, Giovanni
大脑中的细胞活动取决于线粒体提供的高能支持，线粒体是使用能量来源产生ATP的细胞器（1-4）。急性大麻素中毒可诱导人类和动物的健忘症（5，6），并且存在于脑线粒体膜（mtCB（1））的1型大麻素受体的激活可直接改变线粒体能量活动（7-9）。虽然脑中慢性线粒体功能障碍的病理学影响已得到充分证实（1，2），但线粒体活性的急性调节是否参与高脑功能（包括学习和记忆）尚不清楚。在这里，我们表明，急性大麻素诱导的小鼠记忆障碍需要激活海马mtCB（1）受体。海马线粒体中CB 1受体的遗传排斥可防止大麻素诱导的线粒体迁移率、突触传递和记忆形成的降低。mtCB（1）受体通过线粒体内G alpha（i）蛋白激活和随后的可溶性腺苷酸环化酶（sAC）抑制发出信号。线粒体电子传递系统的特定亚基的蛋白激酶A（PKA）依赖性磷酸化的抑制最终导致细胞呼吸降低。海马抑制sAC活性或操纵线粒体内PKA信号传导或复合物I亚基NDUFS 2的磷酸化抑制大麻素的生物能量和遗忘作用。因此，G蛋白偶联的mtCB（1）受体通过调节线粒体能量代谢来调节记忆过程。通过将线粒体活动与记忆形成直接联系起来，这些数据揭示了生物能量过程是认知功能的主要急性调节器。
Cellular activity in the brain depends on the high energetic support provided by mitochondria, the cell organelles which use energy sources to generate ATP(1-4). Acute cannabinoid intoxication induces amnesia in humans and animals(5,6), and the activation of type-1 cannabinoid receptors present at brain mitochondria membranes (mtCB(1)) can directly alter mitochondrial energetic activity(7-9). Although the pathological impact of chronic mitochondrial dysfunctions in the brain is well established(1,2), the involvement of acute modulation of mitochondrial activity in high brain functions, including learning and memory, is unknown. Here, we show that acute cannabinoid-induced memory impairment in mice requires activation of hippocampal mtCB(1) receptors. Genetic exclusion of CB1 receptors from hippocampal mitochondria prevents cannabinoid-induced reduction of mitochondrial mobility, synaptic transmission and memory formation. mtCB(1) receptors signal through intra-mitochondrial G alpha(i) protein activation and consequent inhibition of soluble-adenylyl cyclase (sAC). The resulting inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system eventually leads to decreased cellular respiration. Hippocampal inhibition of sAC activity or manipulation of intra-mitochondrial PKA signalling or phosphorylation of the Complex I subunit NDUFS2 inhibit bioenergetic and amnesic effects of cannabinoids. Thus, the G protein-coupled mtCB(1) receptors regulate memory processes via modulation of mitochondrial energy metabolism. By directly linking mitochondrial activity to memory formation, these data reveal that bioenergetic processes are primary acute regulators of cognitive functions.