Impaired chemosensitivity of mouse dorsal raphe serotonergic neurons overexpressing serotonin 1A (Htr1a) receptors.
Impaired chemosensitivity of mouse dorsal raphe serotonergic neurons overexpressing serotonin 1A (Htr1a) receptors.
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DOI：
10.1371/journal.pone.0045072
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Corradetti R
中科院分区：
文献类型：
--
作者：
Baccini G;Mlinar B;Audero E;Gross CT;Corradetti R
5-羟色胺能系统参与多种生理过程和行为，但其作用通常被认为是调节性的和非决定性的，尤其是在维持生命的功能方面。我们最近创建了一个转基因小鼠系，其中由于过度的5-羟色胺自抑制而产生的5-羟色胺稳态功能缺陷是通过诱导5-羟色胺1A受体（Htr 1a）选择性过表达在多巴胺能神经元（Htr 1a中缝过度表达或Htr 1aRO小鼠）。Htr 1aRO小鼠表现出自主神经失调，心血管危象和死亡的事件，类似于婴儿猝死综合征（SIDS），并揭示了维生素C能系统在自主神经控制中的生命支持作用。由于中脑多巴胺能神经元是化学敏感的，并与唤醒有关，我们假设它们的化学敏感性可能在Htr 1aRO小鼠中受损。脑干切片中的松密封细胞贴附记录显示，Htr 1aRO小鼠中缝背核中的多巴胺能神经元对高碳酸血症的反应与对照组相比显著降低。在对照组小鼠中，应用9%的CO2使多巴胺能神经元的放电频率增加（0.260±0.041 Hz，n = 20，p = 0.0001），应用3%的CO2降低了它们的放电频率（−0.142±0.025 Hz，n = 17，p = 0.0008）。 相比之下，在Htr 1aRO小鼠中，9%CO2（0.021±0.034 Hz，n = 16，p = 0.49）和3%CO2（0.012±0.046 Hz，n = 12，p = 0.97）未显著改变多巴胺能神经元的放电率。 我们的研究结果支持了这一假设，即化学敏感性的中脑肾上腺素能神经元提供了一种生理机制，唤醒反应，危及生命的高碳酸血症发作和功能障碍，如过度的自抑制，中脑肾上腺素能神经元的反应，高碳酸血症可能会导致猝死。
Serotonergic system participates in a wide range of physiological processes and behaviors, but its role is generally considered as modulatory and noncrucial, especially concerning life-sustaining functions. We recently created a transgenic mouse line in which a functional deficit in serotonin homeostasis due to excessive serotonin autoinhibition was produced by inducing serotonin 1A receptor (Htr1a) overexpression selectively in serotonergic neurons (Htr1a raphe-overexpressing or Htr1aRO mice). Htr1aRO mice exhibit episodes of autonomic dysregulation, cardiovascular crises and death, resembling those of sudden infant death syndrome (SIDS) and revealing a life-supporting role of serotonergic system in autonomic control. Since midbrain serotonergic neurons are chemosensitive and are implicated in arousal we hypothesized that their chemosensitivity might be impaired in Htr1aRO mice. Loose-seal cell-attached recordings in brainstem slices revealed that serotonergic neurons in dorsal raphe nucleus of Htr1aRO mice have dramatically reduced responses to hypercapnic challenge as compared with control littermates. In control mice, application of 9% CO2 produced an increase in firing rate of serotonergic neurons (0.260±0.041 Hz, n = 20, p = 0.0001) and application of 3% CO2 decreased their firing rate (−0.142±0.025 Hz, n = 17, p = 0.0008). In contrast, in Htr1aRO mice, firing rate of serotonergic neurons was not significantly changed by 9% CO2 (0.021±0.034 Hz, n = 16, p = 0.49) and by 3% CO2 (0.012±0.046 Hz, n = 12, p = 0.97). Our findings support the hypothesis that chemosensitivity of midbrain serotonergic neurons provides a physiological mechanism for arousal responses to life-threatening episodes of hypercapnia and that functional impairment, such as excessive autoinhibition, of midbrain serotonergic neuron responses to hypercapnia may contribute to sudden death.
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DOI：
10.1523/jneurosci.1963-09.2009
发表时间：
2009-08-19
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Hodges MR;Wehner M;Aungst J;Smith JC;Richerson GB
通讯作者：
Richerson GB
影响因子：
2.3
作者：
Corcoran, Andrea E.;Hodges, Matthew R.;Wu, Yuanming;Wang, Wengang;Wylie, Christie J.;Deneris, Evan S.;Richerson, George B.
通讯作者：
Richerson, George B.
DOI：
10.1126/science.1205295
发表时间：
2011-07-29
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Ray RS;Corcoran AE;Brust RD;Kim JC;Richerson GB;Nattie E;Dymecki SM
通讯作者：
Dymecki SM
影响因子：
3.3
作者：
BERTHONJONES, M;SULLIVAN, CE
通讯作者：
SULLIVAN, CE
影响因子：
5.5
作者：
Cummings, Kevin J.;Hewitt, Julie C.;Nattie, Eugene E.
通讯作者：
Nattie, Eugene E.