Experimental Biology Division, Defence Institute of High Altitude Research, Defence Research and Development Organisation, c/o 56 APO, Leh-Ladakh, Jammu & Kashmir, Pin-901205, India.
Department of Physiology, All India Institute of Medical Sciences, Bhubaneswar, India.
Mol Neurobiol. 2017 Oct;54(8):6133-6147. doi: 10.1007/s12035-016-0156-0. Epub 2016 Oct 3.
Exposure to global hypoxia and ischemia has been reported to cause neurodegeneration in the hippocampus with CA3 neurons. This neuronal damage is progressive during the initial phase of exposure but maintains a plateau on prolonged exposure. The present study on Sprague Dawley rats aimed at understanding the underlying molecular and epigenetic mechanisms that lead to hypoxic adaptation of CA3 neurons on prolonged exposure to a global hypoxia. Our results show stagnancy in neurodegeneration in CA3 region beyond 14 days of chronic exposure to hypobaria simulating an altitude of 25,000 ft. Despite increased synaptosomal glutamate and higher expression of NR1 subunit of NMDA receptors, we observed decrease in post-synaptic density and accumulation of synaptic vesicles at the pre-synaptic terminals. Molecular investigations involving western blot and real-time PCR showed duration-dependent decrease in the expression of SNAP-25 resulting in reduced vesicular docking and synaptic remodeling. ChIP assays for epigenetic factors showed decreased expression of H3K9Ac and H3K14Ac resulting in SNAP-25 promoter silencing during prolonged hypoxia. Administration of sodium butyrate, a non-specific HDAC inhibitor, during 21 days hypoxic exposure prevented SNAP-25 downregulation but increased CA3 neurodegeneration. This epigenetic regulation of SNAP-25 promoter was independent of increased DNMT3b expression and promoter methylation. Our findings provide a novel insight into epigenetic factors-mediated synaptic remodeling to prevent excitotoxic neurodegeneration on prolonged exposure to global hypobaric hypoxia.
已有研究报道，全球缺氧和缺血会导致海马 CA3 神经元发生神经退行性变。这种神经元损伤在暴露初期呈进行性发展，但在长时间暴露后会保持稳定。本研究以 Sprague Dawley 大鼠为研究对象，旨在探讨导致 CA3 神经元在长时间暴露于模拟 25000 英尺高空的低氧环境下产生低氧适应的潜在分子和表观遗传机制。我们的研究结果表明，在慢性低氧暴露 14 天后，CA3 区的神经退行性变趋于停滞。尽管突触小体谷氨酸增加，NMDA 受体 NR1 亚基表达升高，但我们观察到突触后密度降低，突触前末梢的突触小泡堆积。涉及 Western blot 和实时 PCR 的分子研究表明，SNAP-25 的表达随时间的推移呈下降趋势，导致囊泡对接和突触重塑减少。针对表观遗传因子的 ChIP 检测显示，H3K9Ac 和 H3K14Ac 的表达减少，导致 SNAP-25 启动子沉默，从而在长时间低氧暴露期间抑制其表达。在 21 天低氧暴露期间给予非特异性组蛋白去乙酰化酶抑制剂丁酸钠可防止 SNAP-25 下调，但会增加 CA3 神经退行性变。这种 SNAP-25 启动子的表观遗传调控不依赖于 DNMT3b 表达增加和启动子甲基化。我们的研究结果为深入了解表观遗传因子介导的突触重塑机制，以预防长时间暴露于全球低氧环境下的兴奋性神经退行性变提供了新的认识。
