Protein Tyrosine Phosphatase sigma Inhibitory Peptide Promotes Recovery of Diaphragm Function and Sprouting of Bulbospinal Respiratory Axons after Cervical Spinal Cord Injury

摘要

Damage to respiratory neural circuitry and consequent loss of diaphragm function is a major cause of morbidity and mortality after cervical spinal cord injury (SCI). Upon SCI, inspiratory signals originating in the medullary rostral ventral respiratory group (rVRG) become disrupted from their phrenic motor neuron (PhMN) targets, resulting in diaphragm paralysis. Limited growth of both damaged and spared axon populations occurs after central nervous system trauma attributed, in part, to expression of various growth inhibitory molecules, some that act through direct interaction with the protein tyrosine phosphatase sigma (PTP sigma) receptor located on axons. In the rat model of C2 hemisection SCI, we aimed to block PTP sigma signaling to investigate potential mechanisms of axon plasticity and respiratory recovery using a small molecule peptide mimetic that inhibits PTP sigma. The peptide was soaked into a biocompatible gelfoam and placed directly over the injury site immediately after hemisection and replaced with a freshly soaked piece 1 week post-SCI. At 8 weeks post-hemisection, PTP sigma peptide significantly improved ipsilateral hemidiaphragm function, as assessed in vivo with electromyography recordings. PTP sigma peptide did not promote regeneration of axotomized rVRG fibers originating in ipsilateral medulla, as assessed by tracing after adeno-associated virus serotype 2/mCherry injection into the rVRG. Conversely, PTP sigma peptide stimulated robust sprouting of contralateral-originating rVRG fibers and serotonergic axons within the PhMN pool ipsilateral to hemisection. Further, relesion through the hemisection did not compromise diaphragm recovery, suggesting that PTP sigma peptide-induced restoration of function was attributed to plasticity of spared axon pathways descending in contralateral spinal cord. These data demonstrate that inhibition of PTP sigma signaling can promote significant recovery of diaphragm function after SCI by stimulating plasticity of critical axon populations spared by the injury and consequently enhancing descending excitatory input to PhMNs.