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The Journal of Neuroscience, February 27, 2008, 28(9):2033-2042; doi:10.1523/JNEUROSCI.3570-07.2008

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Development/Plasticity/Repair
Spinal Adenosine A2a Receptor Activation Elicits Long-Lasting Phrenic Motor Facilitation

Francis J. Golder, Lavanya Ranganathan, Irawan Satriotomo, Michael Hoffman, Mary Rachael Lovett-Barr, Jyoti J. Watters, Tracy L. Baker-Herman, and Gordon S. Mitchell

Department of Comparative Biosciences, University of Wisconsin, Madison, Wisconsin 53706

Correspondence should be addressed to Prof. Gordon S. Mitchell, Department of Comparative Biosciences, University of Wisconsin, 2015 Linden Drive, Madison, WI 53706. Email: mitchell{at}svm.vetmed.wisc.edu

Acute intermittent hypoxia elicits a form of spinal, brain-derived neurotrophic factor (BDNF)-dependent respiratory plasticity known as phrenic long-term facilitation. Ligands that activate Gs-protein-coupled receptors, such as the adenosine 2a receptor, mimic the effects of neurotrophins in vitro by transactivating their high-affinity receptor tyrosine kinases, the Trk receptors. Thus, we hypothesized that A2a receptor agonists would elicit phrenic long-term facilitation by mimicking the effects of BDNF on TrkB receptors. Here we demonstrate that spinal A2a receptor agonists transactivate TrkB receptors in the rat cervical spinal cord near phrenic motoneurons, thus inducing long-lasting (hours) phrenic motor facilitation. A2a receptor activation increased phosphorylation and new synthesis of an immature TrkB protein, induced TrkB signaling through Akt, and strengthened synaptic pathways to phrenic motoneurons. RNA interference targeting TrkB mRNA demonstrated that new TrkB protein synthesis is necessary for A2a-induced phrenic motor facilitation. A2a receptor activation also increased breathing in unanesthetized rats, and improved breathing in rats with cervical spinal injuries. Thus, small, highly permeable drugs (such as adenosine receptor agonists) that transactivate TrkB receptors may provide an effective therapeutic strategy in the treatment of patients with ventilatory control disorders, such as obstructive sleep apnea, or respiratory insufficiency after spinal injury or during neurodegenerative diseases.

Key words: plasticity; breathing; neurotrophin; adenosine; transactivation; phrenic

Received Aug. 6, 2007; revised Jan. 13, 2008; accepted Jan. 14, 2008.

Correspondence should be addressed to Prof. Gordon S. Mitchell, Department of Comparative Biosciences, University of Wisconsin, 2015 Linden Drive, Madison, WI 53706. Email: mitchell{at}svm.vetmed.wisc.edu






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