PMID- 29513151 OWN - NLM STAT- MEDLINE DCOM- 20190717 LR - 20200930 IS - 1522-1598 (Electronic) IS - 0022-3077 (Print) IS - 0022-3077 (Linking) VI - 119 IP - 6 DP - 2018 Jun 1 TI - Systemic inflammation inhibits serotonin receptor 2-induced phrenic motor facilitation upstream from BDNF/TrkB signaling. PG - 2176-2185 LID - 10.1152/jn.00378.2017 [doi] AB - Although systemic inflammation induced by even a low dose of lipopolysaccharide (LPS, 100 mug/kg) impairs respiratory motor plasticity, little is known concerning cellular mechanisms giving rise to this inhibition. Phrenic motor facilitation (pMF) is a form of respiratory motor plasticity elicited by pharmacological agents applied to the cervical spinal cord, or by acute intermittent hypoxia (AIH; 3, 5-min hypoxic episodes); when elicited by AIH, pMF is known as phrenic long-term facilitation (pLTF). AIH consisting of moderate hypoxic episodes (mAIH, arterial Po(2) = 35-55 mmHg) elicits pLTF via the Q pathway to pMF, a mechanism that requires spinal serotonin (5HT(2)) receptor activation and new brain-derived neurotrophic factor (BDNF) protein synthesis. Although mild systemic inflammation attenuates mAIH-induced pLTF via spinal p38 MAP kinase activation, little is known concerning how p38 MAP kinase activity inhibits the Q pathway. Here, we confirmed that 24 h after a low LPS dose (100 mug/kg ip), mAIH-induced pLTF is greatly attenuated. Similarly, pMF elicited by intrathecal cervical injections of 5HT(2A) (DOI; 100 muM; 3 x 6 mul) or 5HT(2B) receptor agonists (BW723C86; 100 muM; 3 x 6 mul) is blocked 24 h post-LPS. When pMF was elicited by intrathecal BDNF (100 ng, 12 mul), pMF was actually enhanced 24 h post-LPS. Thus 5HT(2A/2B) receptor-induced pMF is impaired downstream from 5HT(2) receptor activation, but upstream from BDNF/TrkB signaling. Mechanisms whereby LPS augments BDNF-induced pMF are not yet known. NEW & NOTEWORTHY These experiments give novel insights concerning mechanisms whereby systemic inflammation undermines serotonin-dependent, spinal respiratory motor plasticity, yet enhances brain-derived neurotrophic factor (BDNF)/TrkB signaling in phrenic motor neurons. These insights may guide development of new strategies to elicit functional recovery of breathing capacity in patients with respiratory impairment by reducing (or bypassing) the impact of systemic inflammation characteristic of clinical disorders that compromise breathing. FAU - Agosto-Marlin, Ibis M AU - Agosto-Marlin IM AD - Department of Comparative Biosciences, University of Wisconsin , Madison, Wisconsin. FAU - Nichols, Nicole L AU - Nichols NL AD - Department of Comparative Biosciences, University of Wisconsin , Madison, Wisconsin. FAU - Mitchell, Gordon S AU - Mitchell GS AD - Department of Comparative Biosciences, University of Wisconsin , Madison, Wisconsin. AD - Center for Respiratory Research and Rehabilitation, Department of Physical Therapy and McKnight Brain Institute, University of Florida , Gainesville, Florida. LA - eng GR - K99 HL119606/HL/NHLBI NIH HHS/United States GR - R00 HL119606/HL/NHLBI NIH HHS/United States GR - R01 HL069064/HL/NHLBI NIH HHS/United States GR - R01 HL111598/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180307 PL - United States TA - J Neurophysiol JT - Journal of neurophysiology JID - 0375404 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Lipopolysaccharides) RN - 0 (Receptors, Serotonin, 5-HT2) RN - EC 2.7.10.1 (Ntrk2 protein, rat) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Hypoxia/*metabolism/physiopathology MH - Inflammation/etiology/metabolism MH - Lipopolysaccharides/toxicity MH - Male MH - Motor Neurons/*metabolism/physiology MH - Phrenic Nerve/*metabolism/physiology MH - Rats MH - Rats, Sprague-Dawley MH - Receptor, trkB/*metabolism MH - Receptors, Serotonin, 5-HT2/*metabolism MH - Signal Transduction MH - Spinal Cord/metabolism/physiology MH - p38 Mitogen-Activated Protein Kinases/metabolism PMC - PMC6032128 OTO - NOTNLM OT - 5HT2A OT - 5HT2B OT - hypoxia OT - intermittent OT - long-term facilitation OT - motor neuron OT - phrenic OT - respiratory plasticity OT - serotonin EDAT- 2018/03/08 06:00 MHDA- 2019/07/18 06:00 PMCR- 2019/06/01 CRDT- 2018/03/08 06:00 PHST- 2018/03/08 06:00 [pubmed] PHST- 2019/07/18 06:00 [medline] PHST- 2018/03/08 06:00 [entrez] PHST- 2019/06/01 00:00 [pmc-release] AID - JN-00378-2017 [pii] AID - 10.1152/jn.00378.2017 [doi] PST - ppublish SO - J Neurophysiol. 2018 Jun 1;119(6):2176-2185. doi: 10.1152/jn.00378.2017. Epub 2018 Mar 7.