Respiratory axon regeneration in the chronically injured spinal cord

NEUROBIOLOGY OF DISEASE

卷:155

Article

Cheng, Lan¹  Sami, Armin¹  Ghosh, Biswarup¹  Goudsward, Hannah J.²  Smith, George M.³  Wright, Megan C.²  Li, Shuxin³  Lepore, Angelo C.¹ 

[1] Thomas Jefferson Univ, Sidney Kimmel Med Coll, Vickie & Jack Farber Inst Neurosci, Dept Neurosci, 233 South 10th St,BLSB 245, Philadelphia, PA 19107 USA

[2] Arcadia Univ, Dept Biol, 450 S Easton Rd,220 Boyer Hall, Glenside, PA 19038 USA

[3] Temple Univ, Shriners Hosp Pediat Res Ctr, Dept Neurosci, Sch Med, 3500 North Broad St, Philadelphia, PA 19140 USA

关键词: SCI;    Spinal cord injury;    Chronic;    Cervical;    Regeneration;    Regrowth;    Diaphragm;    Respiratory;    Breathing;    PTEN;   

DOI  :  10.1016/j.nbd.2021.105389

来源: Elsevier

【 摘 要 】

Promoting the combination of robust regeneration of damaged axons and synaptic reconnection of these growing axon populations with appropriate neuronal targets represents a major therapeutic goal following spinal cord injury (SCI). A key impediment to achieving this important aim includes an intrinsic inability of neurons to extend axons in adult CNS, particularly in the context of the chronically-injured spinal cord. We tested whether an inhibitory peptide directed against phosphatase and tensin homolog (PTEN: a central inhibitor of neuronintrinsic axon growth potential) could restore inspiratory diaphragm function by reconnecting critical respiratory neural circuitry in a rat model of chronic cervical level 2 (C2) hemisection SCI. We found that systemic delivery of PTEN antagonist peptide 4 (PAP4) starting at 8 weeks after C2 hemisection promoted substantial, long-distance regeneration of injured bulbospinal rostral Ventral Respiratory Group (rVRG) axons into and through the lesion and back toward phrenic motor neurons (PhMNs) located in intact caudal C3-C5 spinal cord. Despite this robust rVRG axon regeneration, PAP4 stimulated only minimal recovery of diaphragm function. Furthermore, re-lesion through the hemisection site completely removed PAP4-induced functional improvement, demonstrating that axon regeneration through the lesion was responsible for this partial functional recovery. Interestingly, there was minimal formation of putative excitatory monosynaptic connections between regrowing rVRG axons and PhMN targets, suggesting that (1) limited rVRG-PhMN synaptic reconnectivity was responsible at least in part for the lack of a significant functional effect, (2) chronically-injured spinal cord presents an obstacle to achieving synaptogenesis between regenerating axons and post-synaptic targets, and (3) addressing this challenge is a potentially-powerful strategy to enhance therapeutic efficacy in the chronic SCI setting. In conclusion, our study demonstrates a non-invasive and transient pharmacological approach in chronic SCI to repair the critically-important neural circuitry controlling diaphragmatic respiratory function, but also sheds light on obstacles to circuit plasticity presented by the chronically-injured spinal cord.