Vglut2-based glutamatergic signaling in central noradrenergic neurons is dispensable for normal breathing and chemosensory reflexes.
Vglut2-based glutamatergic signaling in central noradrenergic neurons is dispensable for normal breathing and chemosensory reflexes.
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中枢去甲肾上腺素能神经元中基于 Vglut2 的谷氨酸信号传导对于正常呼吸和化学感应反射是可有可无的。
DOI：
10.1101/2023.04.16.535729
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Ray,RussellS
中科院分区：
文献类型：
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作者：
Chang,Yuan;Lusk,Savannah;Chang,Andersen;Ward,ChristopherS;Ray,RussellS
中枢去甲肾上腺素能（NA）神经元是呼吸稳态网络的关键成分。NA功能障碍涉及几种发育性呼吸障碍，包括先天性中枢过度通气综合征（CCHS）、婴儿猝死综合征（SIDS）和Rett综合征。该领域目前未受挑战的范例，由多项研究支持，是中枢NA神经元亚群中的谷氨酸共传递在呼吸控制中起作用。如果这是真的，那么NA-谷氨酸共传递在呼吸系统疾病中也可能是重要的机制。然而，呼吸中NA衍生的谷氨酸的需求尚未直接测试，并且中央NA系统中谷氨酸共传递的程度仍然没有表征。因此，我们充分表征了NA神经元中所有三种囊泡谷氨酸转运蛋白（Slc 17 a7（VEGF 1），Slc 17 a6（VEGF 2）和Slc 17 a8（VEGF 3））的累积命运图和急性成人表达模式，确定了NA系统中VEGF 2的一种新的动态表达模式和VEGF 3的一个未描述的共表达结构域。与我们最初的假设NA衍生的谷氨酸是呼吸所必需的相反，我们的功能研究表明，在无限制和未麻醉的小鼠中，在室内空气、高碳酸血症或缺氧下，整个NA系统中VEGF 2的丢失未能改变呼吸或代谢。这些数据表明，在中枢NA系统内的VEGF 2-基神经元能信号传导对于正常基线呼吸和高碳酸血症、低氧化学感觉反射是不需要的。这些结果挑战了目前对中枢NA神经元控制呼吸的理解，并表明谷氨酸可能不是理解呼吸系统疾病中NA神经元功能障碍的关键目标。
Central noradrenergic (NA) neurons are key constituents of the respiratory homeostatic network. NA dysfunction is implicated in several developmental respiratory disorders including Congenital Central Hyperventilation Syndrome (CCHS), Sudden Infant Death Syndrome (SIDS), and Rett Syndrome. The current unchallenged paradigm in the field, supported by multiple studies, is that glutamate co-transmission in subsets of central NA neurons plays a role in breathing control. If true, NA-glutamate co-transmission may also be mechanistically important in respiratory disorders. However, the requirement of NA-derived glutamate in breathing has not been directly tested and the extent of glutamate co-transmission in the central NA system remains uncharacterized. Therefore, we fully characterized the cumulative fate maps and acute adult expression patterns of all three vesicular glutamate transporters (Slc17a7 (Vglut1), Slc17a6 (Vglut2), and Slc17a8 (Vglut3)) in NA neurons, identifying a novel, dynamic expression pattern for Vglut2 and an undescribed co-expression domain for Vglut3 in the NA system. In contrast to our initial hypothesis that NA-derived glutamate is required to breathing, our functional studies showed that loss of Vglut2 throughout the NA system failed to alter breathing or metabolism under room air, hypercapnia, or hypoxia in unrestrained and unanesthetized mice. These data demonstrate that Vglut2-based glutamatergic signaling within the central NA system is not required for normal baseline breathing and hypercapnic, hypoxic chemosensory reflexes. These outcomes challenge the current understanding of central NA neurons in the control of breathing and suggests that glutamate may not be a critical target to understand NA neuron dysfunction in respiratory diseases.