title: Phrenic long-term facilitation requires PKCθ activity within phrenic motor neurons.
abstract: Acute intermittent hypoxia (AIH) induces a form of spinal motor plasticity known as phrenic long-term facilitation (pLTF); pLTF is a prolonged increase in phrenic motor output after AIH has ended. In anesthetized rats, we demonstrate that pLTF requires activity of the novel PKC isoform, PKCθ, and that the relevant PKCθ is within phrenic motor neurons. Whereas spinal PKCθ inhibitors block pLTF, inhibitors targeting other PKC isoforms do not. PKCθ is highly expressed in phrenic motor neurons, and PKCθ knockdown with intrapleural siRNAs abolishes pLTF. Intrapleural siRNAs targeting PKCζ, an atypical PKC isoform expressed in phrenic motor neurons that underlies a distinct form of phrenic motor plasticity, does not affect pLTF. Thus, PKCθ plays a critical role in spinal AIH-induced respiratory motor plasticity, and the relevant PKCθ is localized within phrenic motor neurons. Intrapleural siRNA delivery has considerable potential as a therapeutic tool to selectively manipulate plasticity in vital respiratory motor neurons.
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, Wisconsin 53562.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Devinney
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, Wisconsin 53562.
authors.forename: Daryl P
authors.initials: DP
authors.lastname: Fields
authors.affiliation: Department of Human Physiology, University of Oregon, Eugene, Oregon 97403.
authors.forename: Adrianne G
authors.initials: AG
authors.lastname: Huxtable
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, Wisconsin 53562.
authors.forename: Timothy J
authors.identifier: http://orcid.org/0000-0003-0995-3644
authors.initials: TJ
authors.lastname: Peterson
authors.affiliation: Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, California 90095, and.
authors.forename: Erica A
authors.initials: EA
authors.lastname: Dale
authors.affiliation: McKinight Brain Institute, Department of Physical Therapy, College of Public Health & Health Professions, University of Florida, Gainesville, Florida 32610 mitchell@svm.vetmed.wisc.edu.
authors.forename: Gordon S
authors.identifier: http://orcid.org/0000-0002-8489-1861
authors.initials: GS
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D000860:Hypoxia / Q000201:enzymology* / Q000503:physiopathology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009046:Motor Neurons / Q000187:drug effects / Q000201:enzymology*; D010791:Phrenic Nerve / Q000187:drug effects / Q000201:enzymology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000074121:Protein Kinase C-theta; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; C489591:Prkcq protein, rat; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta
keywords: intermittent hypoxia; motor neuron; plasticity; protein kinase C; spinal cord