title: Phrenic long-term facilitation after acute intermittent hypoxia requires spinal ERK activation but not TrkB synthesis.
abstract: Acute intermittent hypoxia (AIH) elicits a form of spinal respiratory plasticity known as phrenic long-term facilitation (pLTF). pLTF requires spinal serotonin receptor-2 activation, the synthesis of new brain-derived neurotrophic factor (BDNF), and the activation of its high-affinity receptor tyrosine kinase, TrkB. Spinal adenosine 2A receptor activation elicits a distinct pathway to phrenic motor facilitation (pMF); this BDNF synthesis-independent pathway instead requires new synthesis of an immature TrkB isoform. Since hypoxia increases extracellular adenosine levels, we tested the hypothesis that new synthesis of TrkB and BDNF contribute to AIH-induced pLTF. Furthermore, given that signaling mechanisms "downstream" from TrkB are unknown in either mechanism, we tested the hypothesis that pLTF requires MEK/ERK and/or phosphatidylinositol 3-kinase (PI3K)/Akt activation. In anesthetized Sprague-Dawley rats, an intrathecal catheter at cervical level 4 was used to deliver drugs near the phrenic motor nucleus. Since pLTF was blocked by spinal injections of small interfering RNAs targeting BDNF mRNA but not TrkB mRNA, only new BDNF synthesis is required for AIH-induced pLTF. Pretreatment with a MEK inhibitor (U0126) blocked pLTF, whereas a PI3K inhibitor (PI-828) had no effect. Thus, AIH-induced pLTF requires MEK/ERK (not PI3K/AKT) signaling pathways. When U0126 was injected post-AIH, pLTF development was halted but not reversed, suggesting that ERK is critical for the development but not maintenance of pLTF. Thus, there are clear mechanistic distinctions between AIH-induced pLTF (i.e., BDNF synthesis and MEK/ERK dependent) versus adenosine 2A receptor-induced pMF (i.e., TrkB synthesis and PI3K/Akt dependent).
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin, 2015 Linden Drive, Madison, WI 53706-1102, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Hoffman
authors.forename: N L
authors.initials: NL
authors.lastname: Nichols
authors.forename: P M
authors.initials: PM
authors.lastname: Macfarlane
authors.forename: G S
authors.initials: GS
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D001784:Blood Gas Analysis / Q000379:methods; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002070:Butadienes / Q000494:pharmacology; D000860:Hypoxia / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D007278:Injections, Spinal / Q000379:methods; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics*; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010791:Phrenic Nerve / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D043683:Receptors, Adenosine A2 / Q000235:genetics / Q000378:metabolism; D012137:Respiratory System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002070:Butadienes; D009570:Nitriles; D012333:RNA, Messenger; D043683:Receptors, Adenosine A2; C113580:U 0126; D019869:Phosphatidylinositol 3-Kinases; D020813:Receptor, trkB