Gasotransmitter modulation of hypoglossal motoneuron activity.
Gasotransmitter modulation of hypoglossal motoneuron activity.
复制标题
舌下运动神经元活动的气体递质调节。
DOI：
10.7554/elife.81978
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发表时间：
2023-01-19
期刊：
影响因子：
7.7
通讯作者：
Garcia AJ 3rd
中科院分区：
文献类型：
--
作者：
Browe BM;Peng YJ;Nanduri J;Prabhakar NR;Garcia AJ 3rd
阻塞性睡眠呼吸暂停（OSA）的特征是上呼吸道的偶发性塌陷，导致呼吸周期性中断。上呼吸道的通畅是由颏舌神经活动，起源于舌下神经运动核。具有编码一氧化碳（CO）产生酶血红素加氧酶-2（HO-2）的基因Hmox 2的靶向缺失的小鼠表现出OSA，但中枢HO-2失调对该现象的贡献尚不清楚。使用含有前BötC复合体和舌下神经核的节律性脑干切片制备，我们测试了中枢HO-2失调减弱舌下神经运动神经元输出的假设。破坏HO-2活性增加了前BötC亚网络活动的发生，这与节律发生的不规则性增加有关。这些现象也与前BötC节律间歇性无法驱动舌下神经核的输出（即传输失败）以及前BötC和运动核之间的输入-输出关系减少有关。HO-2失调降低吸气舌下神经元的兴奋性突触电流和内在兴奋性。抑制CO调节的H2S产生酶，胱硫醚-γ-裂解酶（CSE）的活性，减少HO-2缺失脑干切片中的传递失败，这也使兴奋性突触电流和舌下神经运动神经元的内在兴奋性正常化。这些研究结果表明，迄今未表征的调制舌下神经活动通过相互作用的HO-2/CO和CSE/H2S，并支持潜在的重要性，中央衍生的气体递质活性调节上气道控制。
Obstructive sleep apnea (OSA) is characterized by sporadic collapse of the upper airway leading to periodic disruptions in breathing. Upper airway patency is governed by genioglossal nerve activity that originates from the hypoglossal motor nucleus. Mice with targeted deletion of the gene Hmox2, encoding the carbon monoxide (CO) producing enzyme, heme oxygenase-2 (HO-2), exhibit OSA, yet the contribution of central HO-2 dysregulation to the phenomenon is unknown. Using the rhythmic brainstem slice preparation that contains the preBötzinger complex (preBötC) and the hypoglossal nucleus, we tested the hypothesis that central HO-2 dysregulation weakens hypoglossal motoneuron output. Disrupting HO-2 activity increased the occurrence of subnetwork activity from the preBötC, which was associated with an increased irregularity of rhythmogenesis. These phenomena were also associated with the intermittent inability of the preBötC rhythm to drive output from the hypoglossal nucleus (i.e. transmission failures), and a reduction in the input-output relationship between the preBötC and the motor nucleus. HO-2 dysregulation reduced excitatory synaptic currents and intrinsic excitability in inspiratory hypoglossal neurons. Inhibiting activity of the CO-regulated H2S producing enzyme, cystathionine-γ-lyase (CSE), reduced transmission failures in HO-2 null brainstem slices, which also normalized excitatory synaptic currents and intrinsic excitability of hypoglossal motoneurons. These findings demonstrate a hitherto uncharacterized modulation of hypoglossal activity through mutual interaction of HO-2/CO and CSE/H2S, and support the potential importance of centrally derived gasotransmitter activity in regulating upper airway control.