Hyperpolarisationactivated cyclic nucleotide-gated channels regulate the spontaneous firing rate of olfactory receptor neurons and affect glomerular formation in mice.
Hyperpolarisationactivated cyclic nucleotide-gated channels regulate the spontaneous firing rate of olfactory receptor neurons and affect glomerular formation in mice.
复制标题
超极化激活的环核苷酸门控通道调节嗅觉受体神经元的自发放电率并影响小鼠的肾小球形成。
DOI：
10.1113/jphysiol.2012.247361
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Kageyama R & Ohmori H
中科院分区：
文献类型：
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作者：
Nakashima N;Ishii TM;Bessho Y;Kageyama R & Ohmori H
•嗅觉受体神经元（orn）利用自发放电活动进行轴突靶向。•环AMP门控HCN通道使orn膜去极化并增强其自发放电活性。β -肾上腺素能受体的长期激活维持了基础cAMP水平，并导致HCN通道的开放。•HCN4的过表达导致嗅球肾小球数量减少，通过抑制HCN4的过表达来挽救肾小球。•HCN通道与G蛋白偶联受体的持续激活一起，维持了orn的自发放电活性，对嗅球肾小球的形成至关重要。为了了解神经元如何形成精确的拓扑网络，人们对经历终身神经发生的工厂受体神经元（orn）进行了广泛的研究。来自orn的神经投射主要受遗传密码的引导，遗传密码引导来自表达特定气味受体的orn的投射到嗅球中相应的肾小球。此外，神经网络利用自发放电活动来建立和维持神经图谱。然而，产生这种自发活动的过程及其在嗅球中作为引导线索的作用都不清楚。利用小鼠嗅上皮切片的细胞外单位记录，我们证明了在orn的体细胞中，超极化激活的环核苷酸门控（HCN）通道通过感知基础cAMP水平使其膜去极化并提高其自发放电率；纤毛中气味敏感的环核苷酸门控（CNG）通道则没有。通过β -肾上腺素能受体的长期激活维持基础cAMP水平。使用Tet - off系统过表达HCN4通道可增强自发ORN活性，并显著减少嗅球肾小球的大小和数量。这种表型是由强力霉素的管理抢救。这些发现表明cAMP在纤毛和体细胞中发挥着不同的作用，并且体细胞中的基础cAMP水平直接通过HCN通道转化为自发放电频率，作为嗅觉网络形成的内在指导线索。
Key points•Olfactory receptor neurons (ORNs) utilise the spontaneous firing activity for axonal targeting.•Cyclic AMP‐gated HCN channels depolarised the membranes of ORNs and enhanced their spontaneous firing activity.•Standing activation of the β‐adrenergic receptors maintained the basal cAMP level and resulted in the opening of HCN channels.•The over‐expression of HCN4 resulted in a decrease in the number of glomeruli in the olfactory bulb, which was rescued by suppressing HCN4 over‐expression.•HCN channels, together with the standing activation of G‐protein‐coupled receptors, maintained the spontaneous firing activity of ORNs and were essential to glomerular formation in the olfactory bulb.AbstractOlfactory receptor neurons (ORNs), which undergo lifelong neurogenesis, have been studied extensively to understand how neurons form precise topographical networks. Neural projections from ORNs are principally guided by the genetic code, which directs projections from ORNs that express a specific odorant receptor to the corresponding glomerulus in the olfactory bulb. In addition, ORNs utilise spontaneous firing activity to establish and maintain the neural map. However, neither the process of generating this spontaneous activity nor its role as a guidance cue in the olfactory bulb is clearly understood. Utilising extracellular unit‐recordings in mouse olfactory epithelium slices, we demonstrated that the hyperpolarisation‐activated cyclic nucleotide‐gated (HCN) channels in the somas of ORNs depolarise their membranes and boost their spontaneous firing rates by sensing basal cAMP levels; the odorant‐sensitive cyclic nucleotide‐gated (CNG) channels in cilia do not. The basal cAMP levels were maintained via the standing activation of β‐adrenergic receptors. Using a Tet‐off system to over‐express HCN4 channels resulted in the enhancement of spontaneous ORN activity and dramatically reduced both the size and number of glomeruli in the olfactory bulb. This phenotype was rescued by the administration of doxycycline. These findings suggest that cAMP plays different roles in cilia and soma and that basal cAMP levels in the soma are directly converted via HCN channels into a spontaneous firing frequency that acts as an intrinsic guidance cue for the formation of olfactory networks.