Xamoterol impairs hippocampus-dependent emotional memory retrieval via Gi/o-coupled β2-adrenergic signaling.
Xamoterol impairs hippocampus-dependent emotional memory retrieval via Gi/o-coupled β2-adrenergic signaling.
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DOI：
10.1101/lm.2302811
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发表时间：
2011-09
影响因子：
2
通讯作者：
Keith Schutsky;Ouyang Ming;S. Thomas
中科院分区：
文献类型：
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作者：
Keith Schutsky;Ouyang Ming;S. Thomas
沙莫特罗是一种部分β(1)-肾上腺素能受体激动剂，据报道，它会损害大鼠海马依赖的空间参考记忆的检索。相反，在去甲肾上腺素（NE）缺失的基因靶向小鼠和NE水平降低的唐氏综合征转基因小鼠模型中，xamoterol可以恢复记忆。在这两种模型中，沙莫特罗恢复检索补充了NE和β(1)信号是野生型小鼠和大鼠海马依赖的上下文和空间参考记忆检索所必需的。其他证据表明，camp介导的PKA和Epac信号是海马体依赖性记忆检索所必需的。因此，我们假设xamoterol除了刺激β(1)受体外还有其他作用，在高剂量下，可以抵消β(1)信号传导的作用。在这里，我们报道xamoterol诱导的记忆恢复的中断依赖于β(2)-肾上腺素能受体信号。有趣的是，xamoterol对记忆恢复的损害可以通过预处理百日毒（G（i/o）信号解偶联剂）来阻断，这表明在G蛋白和cAMP信号水平上，β(2)信号在记忆恢复过程中与β(1)信号相对抗。最后，与NE、β(1)和cAMP信号在海马依赖性记忆检索中的时间依赖性作用类似，xamoterol仅在训练后几天内损害检索，表明其效果也受到记忆年龄的限制。我们得出结论，xamoterol对记忆检索的破坏是由G（i/o）偶联β(2)信号介导的，这与海马依赖性情绪记忆检索所需的G(s)偶联β(1)信号相反。
Xamoterol, a partial β(1)-adrenergic receptor agonist, has been reported to impair the retrieval of hippocampus-dependent spatial reference memory in rats. In contrast, xamoterol restores memory retrieval in gene-targeted mice lacking norepinephrine (NE) and in a transgenic mouse model of Down syndrome in which NE levels are reduced. Restoration of retrieval by xamoterol in these two models complements the observation that NE and β(1) signaling are required for hippocampus-dependent retrieval of contextual and spatial reference memory in wild-type mice and rats. Additional evidence indicates that cAMP-mediated PKA and Epac signaling are required for the retrieval of hippocampus-dependent memory. As a result, we hypothesized that xamoterol has effects in addition to the stimulation of β(1) receptors that, at higher doses, act to counter the effects of β(1) signaling. Here we report that xamoterol-induced disruption of memory retrieval depends on β(2)-adrenergic receptor signaling. Interestingly, the impairment of memory retrieval by xamoterol is blocked by pretreatment with pertussis toxin, an uncoupling agent for G(i/o) signaling, suggesting that β(2) signaling opposes β(1) signaling during memory retrieval at the level of G protein and cAMP signaling. Finally, similar to the time-dependent roles for NE, β(1), and cAMP signaling in hippocampus-dependent memory retrieval, xamoterol only impairs retrieval for several days after training, indicating that its effects are also limited by the age of the memory. We conclude that the disruption of memory retrieval by xamoterol is mediated by G(i/o)-coupled β(2) signaling, which opposes the G(s)-coupled β(1) signaling that is transiently required for hippocampus-dependent emotional memory retrieval.