Moderate acute intermittent hypoxia (mAIH) elicits a form of phrenic motor plasticity known as phrenic long-term facilitation (pLTF) which requires spinal 5-HT2A receptor activation, ERK/MAP kinase signaling and BDNF synthesis.… Click to show full abstract
Moderate acute intermittent hypoxia (mAIH) elicits a form of phrenic motor plasticity known as phrenic long-term facilitation (pLTF) which requires spinal 5-HT2A receptor activation, ERK/MAP kinase signaling and BDNF synthesis. New BDNF protein activates TrkB receptors that normally signal through PKCθ, leading to pLTF. Phrenic motor plasticity elicited by spinal drug administration (e.g., BDNF) is referred to by a more general term: phrenic motor facilitation (pMF). Although mild systemic inflammation elicited by a low lipopolysaccharide (LPS) dose (100μg/kg) undermines mAIH-induced pLTF upstream from BDNF protein synthesis, it actually augments pMF induced by spinal BDNF administration through unknown mechanisms. Here, we tested the hypothesis that mild inflammation shifts BDNF/TrkB signaling from PKCθ to alternative pathways that enhance pMF. We examined the role of 3 known signaling pathways associated with TrkB (MEK/ERK kinase, PI3 kinase/Akt and PKCθ) in BDNF-induced pMF in anesthetized, paralyzed and ventilated Sprague Dawley rats 24 hours post-LPS. Spinal PKCθ inhibitor (TIP) attenuated early BDNF-induced pMF (≤30 min), with minimal effect 60-90 min post-BDNF injection. In contrast, MEK inhibition (U0126) abolished BDNF-induced pMF at 60 and 90 min. PI3K/Akt inhibition (PI-828) had no effect on BDNF-induced pMF. Thus, whereas BDNF-induced pMF is exclusively PKCθ-dependent in normal rats, MEK/ERK is recruited by neuroinflammation to sustain, and even augment downstream plasticity. Because AIH is being developed as a therapeutic modality to restore breathing in people living with multiple neurological disorders, it is important to understand how inflammation, a common co-morbidity in many traumatic or degenerative CNS disorders, impacts phrenic motor plasticity.
               
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