Abstract
Compromise in inspiratory breathing following cervical spinal cord injury (SCI) is caused by damage to descending bulbospinal axons originating in the rostral ventral respiratory group (rVRG) and consequent denervation and silencing of phrenic motor neurons (PhMNs) that directly control diaphragm activation. In a rat model of high-cervical hemisection SCI, we performed systemic administration of an antagonist peptide directed against phosphatase and tensin homolog (PTEN), a central inhibitor of neuron-intrinsic axon growth potential. PTEN antagonist peptide (PAP4) robustly restored diaphragm function, as determined with electromyography (EMG) recordings in living SCI animals. PAP4 promoted substantial, long-distance regeneration of injured rVRG axons through the lesion and back toward PhMNs located throughout the C3–C5 spinal cord. These regrowing rVRG axons also formed putative excitatory synaptic connections with PhMNs, demonstrating reconnection of rVRG-PhMN-diaphragm circuitry. Lastly, re-lesion through the hemisection site completely ablated functional recovery induced by PAP4. Collectively, our findings demonstrate that axon regeneration in response to systemic PAP4 administration promoted recovery of diaphragmatic respiratory function after cervical SCI.
Footnotes
The authors declare no competing financial interests.
This work was supported by Department of Health and Human Services National Institutes of Health National Institute of Neurological Disorders and Stroke Grants 2R01NS079702-06 (to A.C.L.) and 1F30NS103436 (to B.A.C.), the Craig H. Neilsen Foundation Grant 476686 (to A.C.L.), and the Shriners Hospitals for Children Grant SHC-84051 (to G.M.S.).
↵^ M.W.U. and B.G. share co-first authorship.
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