Differential Roles of Mammalian Target of Rapamycin (mTOR) in Phrenic Long‐Term Facilitation

Abstract

Phrenic long‐term facilitation (pLTF) is a persistent increase in phrenic nerve activity after acute intermittent hypoxia (AIH). This form of spinal plasticity is expressed via distinct cell signaling cascades that depend on the severity of hypoxia during intermittent exposures. Each mechanism requires spinal protein synthesis, though the newly synthesized proteins differ (e.g. BDNF vs immature TrkB). Translational regulation of new protein synthesis is often regulated by mammalian Target of Rapamycin (mTOR)‐dependent translation. Here we tested the hypothesis that mTOR is necessary for severe AIH (sAIH; PaO2 25‐30mmHG), but not moderate AIH (mAIH; PaO2 35‐45mmHG) induced spinal protein synthesis. Phrenic nerve activity was recorded in anesthetized, paralyzed and ventilated male Sprague‐Dawley rats before, during and 60 min after mAIH or sAIH. Rats were pre‐treated with intrathecal injections of vehicle or Rapamycin (0.1mM, 12µl), a highly selective inhibitor of mTOR complex 1. Consistent with our hypothesis, Rapamycin blunted sAIH, but not mAIH induced pLTF. Thus, spinal activation of mTOR and/or its down‐stream targets are necessary for sAIH‐, but not mAIH‐induced pLTF. These results provide further evidence that mAIH and sAIH elicit pLTF via distinct cellular cascades despite differing only in the severity of hypoxemia within hypoxic episodes.