Baker-Herman Tracy L, Fuller David D, Bavis Ryan W, Zabka Andrea G, Golder Francis J, Doperalski Nicholas J, Johnson Rebecca A, Watters Jyoti J, Mitchell Gordon S
Department of Comparative Biosciences, University of Wisconsin, Madison, Wisconsin 53706, USA.
Nat Neurosci. 2004 Jan;7(1):48-55. doi: 10.1038/nn1166. Epub 2003 Dec 14.
Intermittent hypoxia causes a form of serotonin-dependent synaptic plasticity in the spinal cord known as phrenic long-term facilitation (pLTF). Here we show that increased synthesis of brain-derived neurotrophic factor (BDNF) in the spinal cord is necessary and sufficient for pLTF in adult rats. We found that intermittent hypoxia elicited serotonin-dependent increases in BDNF synthesis in ventral spinal segments containing the phrenic nucleus, and the magnitude of these BDNF increases correlated with pLTF magnitude. We used RNA interference (RNAi) to interfere with BDNF expression, and tyrosine kinase receptor inhibition to block BDNF signaling. These disruptions blocked pLTF, whereas intrathecal injection of BDNF elicited an effect similar to pLTF. Our findings demonstrate new roles and regulatory mechanisms for BDNF in the spinal cord and suggest new therapeutic strategies for treating breathing disorders such as respiratory insufficiency after spinal injury. These experiments also illustrate the potential use of RNAi to investigate functional consequences of gene expression in the mammalian nervous system in vivo.
间歇性低氧会在脊髓中引发一种依赖于血清素的突触可塑性，称为膈神经长期易化（pLTF）。在此我们表明，成年大鼠脊髓中脑源性神经营养因子（BDNF）合成增加对于pLTF是必要且充分的。我们发现，间歇性低氧在含有膈神经核的脊髓腹侧节段中引发了依赖于血清素的BDNF合成增加，且这些BDNF增加的幅度与pLTF幅度相关。我们使用RNA干扰（RNAi）来干扰BDNF表达，并使用酪氨酸激酶受体抑制来阻断BDNF信号传导。这些干扰阻断了pLTF，而鞘内注射BDNF则引发了类似于pLTF的效应。我们的研究结果证明了BDNF在脊髓中的新作用和调节机制，并为治疗诸如脊髓损伤后呼吸功能不全等呼吸障碍提出了新的治疗策略。这些实验还说明了RNAi在体内研究哺乳动物神经系统中基因表达功能后果的潜在用途。
