GDNF to the rescue: GDNF delivery effects on motor neurons and nerves, and muscle re-innervation after peripheral nerve injuries

Abstract Peripheral nerve injuries yield devastating consequences, and surgical repair outcomes remain suboptimal. Novel therapeutic strategies such as gene therapy could improve peripheral nerve regeneration. Though adeno-associated virus (AAV) vectors have delivered transgenes to intact peripheral neurons, transduction of transected neurons relevant to management of peripheral nerve injuries has not been reported. Herein, in vivo transduction efficiency of axotomized murine facial neurons using four AAV capsids packaging a fluorescent reporter transgene, tdTomato, is characterized. Proximal stumps of transected facial nerve branches in C57Bl/6J mice were immersed in AAV solutions. Four weeks later, facial motor nuclei were volume-imaged via whole-mount two-photon excitation microscopy, and machine learning-based image segmentation quantified the proportion of transgene expressing neurons. We observed remarkable retrograde transduction efficiency with AAV-PHP.S and AAV-F, with expression levels sufficient to detect intrinsic tdTomato fluorescence. This study confirms successful in vivo retrograde transgene delivery to transected peripheral neurons, an approach that carries potential as a research tool and future therapeutic strategy.

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Peripheral Nerve Injuries of the Shoulder in the Athlete

Clinics in Sports Medicine ◽

10.1016/s0278-5919(20)30735-3 ◽

1990 ◽

Vol 9 (2) ◽

pp. 331-342 ◽

Cited By ~ 4

Author(s):

Francis X. Mendoza ◽

Kenneth Main

Keyword(s):

Peripheral Nerve ◽

Peripheral Nerve Injuries ◽

Nerve Injuries

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Gene Transfer with DNA Strand Technique and Peripheral Nerve Injuries

Journal of Long-Term Effects of Medical Implants ◽

10.1615/jlongtermeffmedimplants.v12.i2.40 ◽

2002 ◽

Vol 12 (2) ◽

pp. 12

Author(s):

Feng Zhang ◽

William C. Lineaweaver

Keyword(s):

Gene Transfer ◽

Peripheral Nerve ◽

Peripheral Nerve Injuries ◽

Nerve Injuries ◽

Dna Strand

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A simple device for the objective evaluation of peripheral nerve injuries

Journal of Hand Surgery (European Volume) ◽

10.1016/0266-7681(86)90198-1 ◽

1986 ◽

Vol 11 (3) ◽

pp. 485 ◽

Cited By ~ 1

Author(s):

P SMITH ◽

G MOTT

Keyword(s):

Peripheral Nerve ◽

Objective Evaluation ◽

Simple Device ◽

Peripheral Nerve Injuries ◽

Nerve Injuries

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Examination of peripheral nerve injuries

Revue Neurologique ◽

10.1016/s0035-3787(07)90470-1 ◽

2007 ◽

Vol 163 (5) ◽

pp. 619

Author(s):

A. Echaniz-Laguna

Keyword(s):

Peripheral Nerve ◽

Peripheral Nerve Injuries ◽

Nerve Injuries

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Permanent central synaptic disconnection of proprioceptors after nerve injury and regeneration. I. Loss of VGLUT1/IA synapses on motoneurons

Journal of Neurophysiology ◽

10.1152/jn.01095.2010 ◽

2011 ◽

Vol 106 (5) ◽

pp. 2450-2470 ◽

Cited By ~ 76

Author(s):

Francisco J. Alvarez ◽

Haley E. Titus-Mitchell ◽

Katie L. Bullinger ◽

Michal Kraszpulski ◽

Paul Nardelli ◽

...

Keyword(s):

Peripheral Nerve ◽

Nerve Injury ◽

Cell Body ◽

Peripheral Nerve Injury ◽

Motor Coordination ◽

Electrophysiological Study ◽

Peripheral Nerve Injuries ◽

Nerve Injuries ◽

Ia Afferent ◽

Axon Collaterals

Motor and sensory proprioceptive axons reinnervate muscles after peripheral nerve transections followed by microsurgical reattachment; nevertheless, motor coordination remains abnormal and stretch reflexes absent. We analyzed the possibility that permanent losses of central IA afferent synapses, as a consequence of peripheral nerve injury, are responsible for this deficit. VGLUT1 was used as a marker of proprioceptive synapses on rat motoneurons. After nerve injuries synapses are stripped from motoneurons, but while other excitatory and inhibitory inputs eventually recover, VGLUT1 synapses are permanently lost on the cell body (75–95% synaptic losses) and on the proximal 100 μm of dendrite (50% loss). Lost VGLUT1 synapses did not recover, even many months after muscle reinnervation. Interestingly, VGLUT1 density in more distal dendrites did not change. To investigate whether losses are due to VGLUT1 downregulation in injured IA afferents or to complete synaptic disassembly and regression of IA ventral projections, we studied the central trajectories and synaptic varicosities of axon collaterals from control and regenerated afferents with IA-like responses to stretch that were intracellularly filled with neurobiotin. VGLUT1 was present in all synaptic varicosities, identified with the synaptic marker SV2, of control and regenerated afferents. However, regenerated afferents lacked axon collaterals and synapses in lamina IX. In conjunction with the companion electrophysiological study [Bullinger KL, Nardelli P, Pinter MJ, Alvarez FJ, Cope TC. J Neurophysiol (August 10, 2011). doi:10.1152/jn.01097.2010], we conclude that peripheral nerve injuries cause a permanent retraction of IA afferent synaptic varicosities from lamina IX and disconnection with motoneurons that is not recovered after peripheral regeneration and reinnervation of muscle by sensory and motor axons.

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Peripheral nerve injuries due to osteochondromas: analysis of 20 cases and review of the literature

Journal of Neurosurgery ◽

10.3171/2013.11.jns13310 ◽

2014 ◽

Vol 120 (5) ◽

pp. 1105-1112 ◽

Cited By ~ 10

Author(s):

Selçuk Göçmen ◽

Ali Kıvanç Topuz ◽

Cem Atabey ◽

Hakan Şimşek ◽

Kenan Keklikçi ◽

...

Keyword(s):

Peripheral Nerve ◽

En Bloc Resection ◽

Bloc Resection ◽

Nerve Compression ◽

Radiographic Evaluation ◽

Peripheral Nerve Injuries ◽

Nerve Injuries ◽

En Bloc ◽

Duration Of Symptoms ◽

Nerve Decompression

Object Nerve compressions due to osteochondromas are extremely rare. The aim of this retrospective study was to investigate the mechanisms, diagnostic evaluations, and treatment of nerve lesions due to osteochondromas, and to review the literature. Methods The authors retrospectively reviewed their clinic data archive from 1998 through 2008, and 20 patients who were operated on due to peripheral nerve injuries caused by osseous growth were enrolled in the study. Patients' age, duration of symptoms, localizations, intraoperative findings, and modified British Medical Research Council (MRC) and electromyography data obtained from hospital records were evaluated. The literature on this topic available in PubMed was also reviewed. All 20 patients underwent surgery, which consisted of tumor excision performed by orthopedic surgeons and nerve decompression performed by neurosurgeons. Results There were 17 men and 3 women included in the study, with a mean age of 21 years (range 18–25 years). Three patients had multiple hereditary exostoses, and 17 had a solitary exostosis. All of the patients underwent en bloc resection. The most common lesion site was the distal femur (45%). The peroneal and posterior tibial nerves were the structures that were affected the most frequently. The mean follow-up was 3.9 years (range 2–7 years). After the surgery, all patients (100%) experienced good sensory recovery (modified MRC Grade S4 or S5). Conclusions To the authors' knowledge, no large series have reported peripheral nerve compression due to exostoses. The authors have several recommendations as a result of their findings. First, all patients with peripheral nerve compression due to an osteochondroma should undergo surgery. Second, preoperative electromyographic examinations and radiographic evaluation, consisting of MRI and CT to provide optimal information about the lesion, are crucially important. Third, immediate treatment is mandatory to regain the best possible recovery. And fourth, performing nerve decompression first and en bloc resection of osteochondroma consecutively in a multidisciplinary fashion is strongly recommended to avoid peripheral nerve injury.

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