Differential signalling induced by α7 nicotinic acetylcholine receptors in hippocampal dentate gyrus in vitro and in vivo.
Differential signalling induced by α7 nicotinic acetylcholine receptors in hippocampal dentate gyrus in vitro and in vivo.
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DOI：
10.1113/jp280505
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Yakel JL
中科院分区：
文献类型：
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作者：
Cheng Q;Lamb P;Stevanovic K;Bernstein BJ;Fry SA;Cushman JD;Yakel JL
α7 烟碱乙酰胆碱受体 (nAChR) 的激活已被证明可以改善海马依赖性学习和记忆。 α7 nAChR 在海马的几种不同细胞类型中密集表达，具有高 Ca2+ 通透性，尽管尚不清楚 α7 nAChR 是否在不同神经元群体之间调动差异信号机制。为了解决这个问题，我们在体外和体内比较了海马齿状区颗粒细胞和 GABA 能神经元之间 α7 nAChR 激动剂诱导的反应（即钙和 cAMP 变化）。在培养的器官型海马切片中，我们观察到激活 α7 nAChR 后，齿状颗粒细胞中的细胞内钙和 cAMP 显着增加。相比之下，GABA能中间神经元在α7 nAChR激活后钙和cAMP浓度几乎没有变化，尽管它们表现出比齿状颗粒细胞大得多的α7 nAChR电流反应。我们发现这是由于 GABA 能中间神经元中 α7 nAChR 诱导的 Ca2+ 升高较小所致。因此，不同细胞类型中 Ca2+ 瞬变的调节导致了随后的细胞内信号级联的差异，并可能导致 α7 nAChR 激活的最终结果。此外，我们通过光纤光度测定法监测体内齿状颗粒细胞和 GABA 能中间神经元的神经元活动。我们观察到给予尼古丁后，齿状颗粒细胞的神经元活动增强，但 GABA 能神经元却没有增强，而 GABA 能神经元在 α7 nAChR 缺陷的颗粒细胞中则不存在。总之，我们揭示了 α7 nAChR 通过细胞类型特异性细胞内信号通路介导的神经元活性增加的机制。
The activation of α7 nicotinic acetylcholine receptors (nAChRs) has been shown to improve hippocampus-dependent learning and memory. α7 nAChRs are densely expressed among several different cell types in the hippocampus, with high Ca2+ permeability, although it is unclear if α7 nAChRs mobilize differential signaling mechanisms among distinct neuronal populations. To address this question, we compared α7 nAChR agonist-induced responses (i.e. calcium and cAMP changes) between granule cells and GABAergic neurons in the hippocampal dentate region both in vitro and in vivo. In cultured organotypic hippocampal slices, we observed robust intracellular calcium and cAMP increases in dentate granule cells upon activation of α7 nAChRs. In contrast, GABAergic interneurons displayed little changes in both calcium and cAMP concentration after α7 nAChR activation, even though they displayed much larger α7 nAChR current responses than that of dentate granule cells. We found that this was due to smaller α7 nAChR-induced Ca2+ rises in GABAergic interneurons. Thus, the regulation of the Ca2+ transients in different cell types resulted in differential subsequent intracellular signaling cascades and likely the ultimate outcome of α7 nAChR activation. Furthermore, we monitored neuronal activities of dentate granule cells and GABAergic interneurons in vivo via optic fiber photometry. We observed enhancement of neuronal activities after nicotine administration in dentate granule cells, but not in GABAergic neurons, which was absent in α7 nAChR-deficient granule cells. In summary, we reveal a mechanism for α7 nAChR-mediated increase of neuronal activity via cell-type specific intracellular signaling pathways.