Mechanisms of Enhanced Phrenic Long-Term Facilitation in SOD1G93A Rats

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
Nicole L NicholsGordon S Mitchell

Abstract

Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease, causing muscle paralysis and death from respiratory failure. Effective means to preserve/restore ventilation are necessary to increase the quality and duration of life in ALS patients. At disease end-stage in a rat ALS model (SOD1G93A ), acute intermittent hypoxia (AIH) restores phrenic nerve activity to normal levels via enhanced phrenic long-term facilitation (pLTF). Mechanisms enhancing pLTF in end-stage SOD1G93A rats are not known. Moderate AIH-induced pLTF is normally elicited via cellular mechanisms that require the following: Gq-protein-coupled 5-HT2 receptor activation, new BDNF synthesis, and MEK/ERK signaling (the Q pathway). In contrast, severe AIH elicits pLTF via a distinct mechanism that requires the following: Gs-protein-coupled adenosine 2A receptor activation, new TrkB synthesis, and PI3K/Akt signaling (the S pathway). In end-stage male SOD1G93A rats and wild-type littermates, we investigated relative Q versus S pathway contributions to enhanced pLTF via intrathecal (C4) delivery of small interfering RNAs targeting BDNF or TrkB mRNA, and MEK/ERK (U0126) or PI3 kinase/Akt (PI828) inhibitors. In anesthetized, paralyzed and ventilated rats...Continue Reading

Citations

Aug 29, 2019·Frontiers in Cellular Neuroscience·Jonu PradhanMark C Bellingham
Aug 22, 2017·Respiratory Physiology & Neurobiology·Nicole L NicholsMiles A Tanner
Nov 9, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Catarina Miranda-LourençoMaria J Diógenes
Aug 8, 2021·Experimental Neurology·Latoya L AllenElisa J Gonzalez-Rothi

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