Recovery from chronic spinal cord contusion after nogo receptor intervention

Wang, Xingxing; Duffy, Philip; McGee, Aaron W.; Hasan, Omar; Gould, Grahame; Tu, Nathan; Harel, Noam Y.; Huang, Yiyun; Carson, Richard E.; Weinzimmer, David; Ropchan, Jim; Benowitz, Larry I.; Cafferty, William B. J.; Strittmatter, Stephen M.

doi:10.1002/ana.22527

Cited by 93 publications

(123 citation statements)

References 71 publications

(211 reference statements)

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“…Antagonizing myelin-based inhibitor signaling has previously shown efficacy in regenerating optic nerve axons following crush injury (31,32,39,40). Here we find that deleting ephrinB3 expression has a similar effect on optic nerve axon regeneration.…”

Section: Discussionsupporting

confidence: 67%

“…Previous experiments have documented increased optic nerve regeneration following ablation or inhibition of signaling mediated by specific myelin-based inhibitory molecules such as NgR1 (31,32). Here we investigated whether a similar phenomenon would be observed after ablation of ephrinB3.…”

Section: Resultsmentioning

confidence: 72%

“…Ablation of ephrinB3-mediated signaling presumably allows EphA4-expressing optic nerve axons to regenerate past the region of the crush site. The extent of regeneration quantified as the number of regenerating axons is approximately sevenfold less than that observed following optic nerve crush in an ngr1 −/− mouse at similar distances from the injury site (32). This difference in regenerative phenotype between mutant strains is likely the result of continued inhibitory signaling through the NgR1 in the ephrinB3 −/− strain.…”

Section: Discussionmentioning

confidence: 83%

“…The optic nerve was crushed 1 mm retroorbitally with forceps, and retinal ganglion cell axon regeneration was analyzed by anterograde CTB tracing at 14 d after crush (31,32).…”

Section: Methodsmentioning

confidence: 99%

“…Given ephrinB3's contribution to myelin inhibition of axon growth in vitro (21) and optic nerve regeneration in vivo, we sought to determine whether functional recovery from spinal cord injury (SCI) might be greater in mice lacking ephrinB3. It has been reported that ephrinB3 −/− mice exhibit a "hopping" movement during locomotion (17,26,27), so we performed detailed analysis of preinjury baseline stepping performance with high-speed video limb kinematics (32,35). Markers placed over each joint of both hindlimbs were tracked pre-and postinjury during unassisted locomotion to provide the most functionally relevant performance.…”

Section: And H-m)mentioning

confidence: 99%

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Myelin-derived ephrinB3 restricts axonal regeneration and recovery after adult CNS injury

Duffy

Wang

Siegel

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Recovery of neurological function after traumatic injury of the adult mammalian central nervous system is limited by lack of axonal growth. Myelin-derived inhibitors contribute to axonal growth restriction, with ephrinB3 being a developmentally important axonal guidance cue whose expression in mature oligodendrocytes suggests a role in regeneration. Here we explored the in vivo regeneration role of ephrinB3 using mice lacking a functional ephrinB3 gene. We confirm that ephrinB3 accounts for a substantial portion of detergent-resistant myelin-derived inhibition in vitro. To assess in vivo regeneration, we crushed the optic nerve and examined retinal ganglion fibers extending past the crush site. Significantly increased axonal regeneration is detected in ephrinB3 −/− mice. Studies of spinal cord injury in ephrinB3 −/− mice must take into account altered spinal cord development and an abnormal hopping gait before injury. In a near-total thoracic transection model, ephrinB3 −/− mice show greater spasticity than wild-type mice for 2 mo, with slightly greater hindlimb function at later time points, but no evidence for axonal regeneration. After a dorsal hemisection injury, increased corticospinal and raphespinal growth in the caudal spinal cord are detected by 6 wk. This increased axonal growth is accompanied by improved locomotor performance measured in the open field and by kinematic analysis. Thus, ephrinB3 contributes to myelin-derived axonal growth inhibition and limits recovery from adult CNS trauma.

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Section: Discussionsupporting

confidence: 67%

Section: Resultsmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 83%

“…The optic nerve was crushed 1 mm retroorbitally with forceps, and retinal ganglion cell axon regeneration was analyzed by anterograde CTB tracing at 14 d after crush (31,32).…”

Section: Methodsmentioning

confidence: 99%

Section: And H-m)mentioning

confidence: 99%

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Myelin-derived ephrinB3 restricts axonal regeneration and recovery after adult CNS injury

Duffy

Wang

Siegel

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Are midsagittal tissue bridges predictive of outcome after cervical spinal cord injury?

Huber

Lachappelle

Sutter

et al. 2017

Annals of Neurology

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T -weighted scans provided data on the extent and dynamics of neuronal tissue damage and midsagittal tissue bridges at the epicenter of traumatic cervical spinal cord lesions in 24 subacute tetraplegic patients. At 1 month postinjury, smaller lesion area and midsagittal tissue bridges identified those patients with lower extremity evoked potentials and better clinical recovery. Wider midsagittal tissue bridges and smaller lesions at 1 month post-injury were associated with neurological and functional recovery at 1-year follow-up. Neuroimaging biomarkers of lesion size and midsagittal tissue bridges are potential outcome predictors and patient stratifiers in both subacute and chronic clinical trials. Ann Neurol 2017;81:740-748.

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Small sensory spinal lesions that affect hand function in monkeys greatly alter primary afferent and motor neuron connections in the cord

Fisher

Garner

Darian‐Smith

2022

J of Comparative Neurology

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Small sensory spinal injuries induce plasticity across the neuraxis, but little is understood about their effect on segmental connections or motor neuron (MN) function.Here, we begin to address this at two levels. First, we compared afferent input distributions from the skin and muscles of the digits with corresponding MN pools to determine their spatial relationship, in both the normal state and 4-6 months after a unilateral dorsal root/dorsal column lesion (DRL/DCL), affecting digits 1-3. Second, we looked at specific changes to MN inputs and membrane properties that likely impact functional recovery. Monkeys received a targeted unilateral DRL/DCL, and 4-6 months later, cholera toxin subunit B (CT-B) was injected bilaterally into either the distal pads of digits 1-3, or related intrinsic hand muscles, to label inputs to the cord, and corresponding MNs. In controls (unlesioned side), cutaneous and proprioceptive afferents from digits 1-3 showed different distribution patterns but similar rostrocaudal spread within the dorsal horn from C1 to T2. In contrast, MNs were distributed across just two segments (C7-8). Following the lesion, sensory inputs were significantly diminished across all 10 segments, though this did not alter MN distributions. Afferent and monoamine inputs, as well as KCC2 cotransporters, were also significantly altered on the cell membrane of CT-B labeled MNs postlesion. In contrast, inhibitory neurotransmission and perineuronal net integrity were not altered at this prechronic timepoint. Our findings indicate that even a small sensory injury can significantly impact sensory and motor spinal neurons and provide new insight into the complex process of recovery.

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Recovery from chronic spinal cord contusion after nogo receptor intervention

Cited by 93 publications

References 71 publications

Myelin-derived ephrinB3 restricts axonal regeneration and recovery after adult CNS injury

Myelin-derived ephrinB3 restricts axonal regeneration and recovery after adult CNS injury

Are midsagittal tissue bridges predictive of outcome after cervical spinal cord injury?

Small sensory spinal lesions that affect hand function in monkeys greatly alter primary afferent and motor neuron connections in the cord

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