Dougherty Brendan J, Fields Daryl P, Mitchell Gordon S
Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, Wisconsin; and.
Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, Wisconsin; and Department of Physical Therapy, University of Florida, Gainesville, Florida.
J Neurophysiol. 2015 Sep;114(3):1784-91. doi: 10.1152/jn.00539.2015. Epub 2015 Jul 29.
Phrenic long-term facilitation (pLTF) is a persistent increase in phrenic nerve activity after acute intermittent hypoxia (AIH). Distinct cell-signaling cascades give rise to pLTF depending on the severity of hypoxemia within hypoxic episodes. Moderate AIH (mAIH; three 5-min episodes, PaO2 ∼35-55 mmHG) elicits pLTF by a serotonin (5-HT)-dependent mechanism that requires new synthesis of brain-derived neurotrophic factor (BDNF), activation of its high-affinity receptor (TrkB), and ERK MAPK signaling. In contrast, severe AIH (sAIH; three 5-min episodes, PaO2 ∼25-30 mmHG) elicits pLTF by an adenosine-dependent mechanism that requires new TrkB synthesis and Akt signaling. Although both mechanisms require spinal protein synthesis, the newly synthesized proteins are distinct, as are the neurochemicals inducing plasticity (serotonin vs. adenosine). In many forms of neuroplasticity, new protein synthesis requires translational regulation via mammalian target of rapamycin (mTOR) signaling. Since Akt regulates mTOR activity, we hypothesized that mTOR activity is necessary for sAIH- but not mAIH-induced pLTF. Phrenic nerve activity in anesthetized, paralyzed, and ventilated rats was recorded before, during, and 60 min after mAIH or sAIH. Rats were pretreated with intrathecal injections of 20% DMSO (vehicle controls) or rapamycin (0.1 mM, 12 μl), a selective mTOR complex 1 inhibitor. Consistent with our hypothesis, rapamycin blocked sAIH- but not mAIH-induced pLTF. Thus spinal mTOR activity is required for adenosine-dependent (sAIH) but not serotonin-dependent (mAIH) pLTF, suggesting that distinct mechanisms regulate new protein synthesis in these forms of spinal neuroplasticity.
膈神经长期易化（pLTF）是急性间歇性缺氧（AIH）后膈神经活动的持续增加。根据缺氧发作期间低氧血症的严重程度，不同的细胞信号级联反应会引发pLTF。中度AIH（mAIH；三个5分钟发作期，动脉血氧分压约35 - 55 mmHg）通过一种依赖5-羟色胺（5-HT）的机制引发pLTF，该机制需要脑源性神经营养因子（BDNF）的新合成、其高亲和力受体（TrkB）的激活以及ERK丝裂原活化蛋白激酶信号传导。相比之下，重度AIH（sAIH；三个5分钟发作期，动脉血氧分压约25 - 30 mmHg）通过一种依赖腺苷的机制引发pLTF，该机制需要TrkB的新合成和Akt信号传导。虽然这两种机制都需要脊髓蛋白合成，但新合成的蛋白质不同，诱导可塑性的神经化学物质（5-羟色胺与腺苷）也不同。在许多形式的神经可塑性中，新蛋白合成需要通过雷帕霉素哺乳动物靶点（mTOR）信号传导进行翻译调控。由于Akt调节mTOR活性，我们假设mTOR活性对于sAIH诱导的pLTF是必需，但对于mAIH诱导的pLTF不是必需的。在mAIH或sAIH之前、期间和之后60分钟记录麻醉、麻痹和通气大鼠的膈神经活动。大鼠经鞘内注射20%二甲亚砜（溶剂对照）或雷帕霉素（0.1 mM，12 μl）（一种选择性mTOR复合物1抑制剂）进行预处理。与我们的假设一致，雷帕霉素阻断了sAIH诱导的pLTF，但未阻断mAIH诱导的pLTF。因此脊髓mTOR活性对于依赖腺苷（sAIH）的pLTF是必需的，但对于依赖5-羟色胺（mAIH）的pLTF不是必需的，这表明不同的机制调节这些形式的脊髓神经可塑性中的新蛋白合成。
