Burgraff Nicholas J, Neumueller Suzanne E, Buchholz Kirstyn J, Hodges Matthew R, Pan Lawrence, Forster Hubert V
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
Physiol Rep. 2019 Apr;7(8):e14035. doi: 10.14814/phy2.14035.
Patients that retain CO in respiratory diseases such as chronic obstructive pulmonary disease (COPD) have worse prognoses and higher mortality rates than those with equal impairment of lung function without hypercapnia. We recently characterized the time-dependent physiologic effects of chronic hypercapnia in goats, which suggested potential neuroplastic shifts in ventilatory control mechanisms. However, little is known about how chronic hypercapnia affects brainstem respiratory nuclei (BRN) that control multiple physiologic functions including breathing. Since many CNS neuroplastic mechanisms include changes in glutamate (AMPA (GluR) and NMDA (GluN)) receptor expression and/or phosphorylation state to modulate synaptic strength and network excitability, herein we tested the hypothesis that changes occur in glutamatergic signaling within BRN during chronically elevated inspired CO (InCO )-hypercapnia. Healthy goats were euthanized after either 24 h or 30 days of chronic exposure to 6% InCO or room air, and brainstems were rapidly extracted for western blot analyses to assess GluR and GluN receptor expression within BRN. Following 24-hr exposure to 6% InCO , GluR or GluN receptor expression were changed from control (P < 0.05) in the solitary complex (NTS & DMV),ventrolateral medulla (VLM), medullary raphe (MR), ventral respiratory column (VRC), hypoglossal motor nucleus (HMN), and retrotrapezoid nucleus (RTN). These neuroplastic changes were not found following 30 days of chronic hypercapnia. However, at 30 days of chronic hypercapnia, there was overall increased (P < 0.05) expression of glutamate receptors in the VRC and RTN. We conclude that time- and site-specific glutamate receptor neuroplasticity may contribute to the concomitant physiologic changes that occur during chronic hypercapnia.
在慢性阻塞性肺疾病（COPD）等呼吸系统疾病中存在二氧化碳潴留的患者，相较于肺功能同等受损但无高碳酸血症的患者，预后更差，死亡率更高。我们最近描述了山羊慢性高碳酸血症的时间依赖性生理效应，这提示通气控制机制可能存在潜在的神经可塑性变化。然而，关于慢性高碳酸血症如何影响控制包括呼吸在内的多种生理功能的脑干呼吸核（BRN），我们知之甚少。由于许多中枢神经系统神经可塑性机制包括谷氨酸（AMPA（GluR）和NMDA（GluN））受体表达和/或磷酸化状态的变化，以调节突触强度和网络兴奋性，因此我们在此测试了这样一个假设，即在慢性吸入二氧化碳（InCO）升高导致的高碳酸血症期间，BRN内的谷氨酸能信号传导会发生变化。健康山羊在慢性暴露于6% InCO或室内空气24小时或30天后实施安乐死，迅速提取脑干用于蛋白质印迹分析，以评估BRN内GluR和GluN受体的表达。在暴露于6% InCO 24小时后，孤束复合体（NTS和DMV）、延髓腹外侧（VLM）、中缝髓质（MR）、腹侧呼吸柱（VRC）、舌下运动核（HMN）和后梯形核（RTN）中的GluR或GluN受体表达与对照组相比发生了变化（P < 0.05）。在慢性高碳酸血症30天后未发现这些神经可塑性变化。然而，在慢性高碳酸血症30天时，VRC和RTN中谷氨酸受体的总体表达增加（P < 0.05）。我们得出结论，时间和位点特异性的谷氨酸受体神经可塑性可能促成了慢性高碳酸血症期间伴随发生的生理变化。
