Chronic intermittent hypoxia induces NMDA receptor-dependent plasticity and suppresses nitric oxide signaling in the mouse hypothalamic paraventricular nucleus.
Chronic intermittent hypoxia induces NMDA receptor-dependent plasticity and suppresses nitric oxide signaling in the mouse hypothalamic paraventricular nucleus.
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DOI：
10.1523/jneurosci.3367-10.2010
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发表时间：
2010-09-08
期刊：
影响因子：
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通讯作者：
Pickel VM
中科院分区：
文献类型：
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作者：
Coleman CG;Wang G;Park L;Anrather J;Delagrammatikas GJ;Chan J;Zhou J;Iadecola C;Pickel VM
慢性间歇性缺氧（CIH）是睡眠呼吸暂停的伴随物，其产生缓慢发展的化学感觉依赖性血压升高，部分归因于NMDA受体依赖性可塑性和颈动脉体中一氧化氮（NO）信号传导减少。下丘脑室旁核（PVN）对缺氧应激有反应，也含有表达NMDA受体和神经元型一氧化氮合酶（nNOS）的神经元。我们测试的假设，延长（35天）CIH的结果在表面/突触的可用性的基本NMDA NR 1亚基的nNOS-含有神经元和NMDA诱导的NO产生的小鼠PVN的减少。与对照组相比，35天CIH暴露的小鼠显示出血压的显著增加和位于含nNOS树突的细胞质中的NR 1免疫金颗粒的密度增加。在14天后没有观察到这些组间差异，即使在这个时间点NR 1质膜密度已经降低。膜片钳记录的PVN神经元切片显示，显着减少NMDA电流后，无论是14或35天暴露于CIH与假对照组相比。与此相反，NO的生产，如测量的NO敏感的荧光染料DAF-FM，仅在35天CIH组被抑制。我们得出结论，CIH产生的表面/nNOS神经元的NR 1的突触靶向减少，并降低NMDA受体介导的电流在PVN出现高血压之前，其发展可能是通过抑制NO信号在这个大脑区域。
Chronic intermittent hypoxia (CIH) is a concomitant of sleep apnea that produces a slowly developing chemosensory-dependent blood pressure elevation ascribed in part to NMDA receptor-dependent plasticity and reduced nitric oxide (NO) signaling in the carotid body. The hypothalamic paraventricular nucleus (PVN) is responsive to hypoxic stress and also contains neurons that express NMDA receptors and neuronal nitric oxide synthase (nNOS). We tested the hypothesis that extended (35 day) CIH results in a decrease in the surface/synaptic availability of the essential NMDA NR1 subunit in nNOS-containing neurons and NMDA-induced NO production in the PVN of mice. As compared with controls, the 35 day CIH-exposed mice showed a significant increase in blood pressure and an increased density of NR1 immunogold particles located in the cytoplasm of nNOS-containing dendrites. Neither of these between-group differences was seen after 14 days, even though there was already a reduction in the NR1 plasmalemmal density at this time point. Patch-clamp recording of PVN neurons in slices showed a significant reduction in NMDA currents after either 14 or 35 day exposure to CIH as compared with sham controls. In contrast, NO production, as measured by the NO-sensitive fluorescent dye DAF-FM, was suppressed only in the 35 day CIH group. We conclude that CIH produces a reduction in the surface/synaptic targeting of NR1 in nNOS neurons and decreases NMDA receptor-mediated currents in the PVN prior to the emergence of hypertension, the development of which may be enabled by suppression of NO signaling in this brain region.