A chronic low dose of Δ9-tetrahydrocannabinol (THC) restores cognitive function in old mice
A chronic low dose of Δ9-tetrahydrocannabinol (THC) restores cognitive function in old mice
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DOI：
10.1038/nm.4311
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发表时间：
2017-06-01
期刊：
影响因子：
82.9
通讯作者：
Zimmer, Andreas
中科院分区：
文献类型：
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作者：
Bilkei-Gorzo, Andras;Albayram, Onder;Zimmer, Andreas
有害的、促进衰老的、通常是随机的过程和抗内稳态机制之间的平衡在很大程度上决定了衰老的进程。有大量证据表明，内源性大麻素系统(ECS)是后者的一部分，因为它调节着衰老的生理过程(1，2)。随着年老动物脑组织中CB1受体的表达和与G蛋白的偶联减少，ECS的活性下降(3-5)，主要的内源性大麻素2-花生四烯基甘油(2-AG)水平降低(6)。然而，内源性大麻素和衰老症状之间的直接联系还没有被证明。在这里，我们证明了低剂量的Delta(9)-四氢大麻酚(THC)逆转了12和18个月龄小鼠认知能力的年龄相关性下降。这种行为效应伴随着突触标记蛋白表达的增强和海马棘密度的增加。THC处理恢复了海马区基因转录模式，使12个月大的THC处理小鼠的表达谱与2个月大的无THC小鼠的表达谱非常相似。THC的转录效应严重依赖于谷氨酸能CB1受体和组蛋白乙酰化，因为它们的抑制阻断了THC的有益作用。因此，在老年人中恢复CB1信号可能是治疗年龄相关性认知障碍的有效策略。
The balance between detrimental, pro-aging, often stochastic processes and counteracting homeostatic mechanisms largely determines the progression of aging. There is substantial evidence suggesting that the endocannabinoid system (ECS) is part of the latter system because it modulates the physiological processes underlying aging(1,2). The activity of the ECS declines during aging, as CB1 receptor expression and coupling to G proteins are reduced in the brain tissues of older animals(3-5) and the levels of the major endocannabinoid 2-arachidonoylglycerol (2-AG) are lower(6). However, a direct link between endocannabinoid tone and aging symptoms has not been demonstrated. Here we show that a low dose of Delta(9)-tetrahydrocannabinol (THC) reversed the age-related decline in cognitive performance of mice aged 12 and 18 months. This behavioral effect was accompanied by enhanced expression of synaptic marker proteins and increased hippocampal spine density. THC treatment restored hippocampal gene transcription patterns such that the expression profiles of THC-treated mice aged 12 months closely resembled those of THC-free animals aged 2 months. The transcriptional effects of THC were critically dependent on glutamatergic CB1 receptors and histone acetylation, as their inhibition blocked the beneficial effects of THC. Thus, restoration of CB1 signaling in old individuals could be an effective strategy to treat age-related cognitive impairments.