Chemotropic guidance facilitates axonal regeneration and synapse formation after spinal cord injury

Laura Taylor Alto; Leif A. Havton; James M. Conner; Edmund R. Hollis; Armin Blesch; Mark H. Tuszynski

doi:10.1038/nn.2365

Chemotropic guidance facilitates axonal regeneration and synapse formation after spinal cord injury

Laura Taylor Alto, Leif A. Havton, James M. Conner, Edmund R. Hollis, Armin Blesch, Mark H. Tuszynski

Neuroscience

Research output: Contribution to journal › Article › peer-review

180 Scopus citations

Abstract

A principal objective of spinal cord injury (SCI) research is the restoration of axonal connectivity to denervated targets. We tested the hypothesis that chemotropic mechanisms would guide regenerating spinal cord axons to appropriate brainstem targets. We subjected rats to cervical level 1 (C1) lesions and combinatorial treatments to elicit axonal bridging into and beyond lesion sites. Lentiviral vectors expressing neurotrophin-3 (NT-3) were then injected into an appropriate brainstem target, the nucleus gracilis, and an inappropriate target, the reticular formation. NT-3 expression in the correct target led to reinnervation of the nucleus gracilis in a dose-related fashion, whereas NT-3 expression in the reticular formation led to mistargeting of regenerating axons. Axons regenerating into the nucleus gracilis formed axodendritic synapses containing rounded vesicles, reflective of pre-injury synaptic architecture. Thus, we report for the first time, to the best of our knowledge, the reinnervation of brainstem targets after SCI and an essential role for chemotropic axon guidance in target selection.

Original language	English (US)
Pages (from-to)	1106-1113
Number of pages	8
Journal	Nature neuroscience
Volume	12
Issue number	9
DOIs	https://doi.org/10.1038/nn.2365
State	Published - Sep 2009

ASJC Scopus subject areas

General Neuroscience

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title = "Chemotropic guidance facilitates axonal regeneration and synapse formation after spinal cord injury",

abstract = "A principal objective of spinal cord injury (SCI) research is the restoration of axonal connectivity to denervated targets. We tested the hypothesis that chemotropic mechanisms would guide regenerating spinal cord axons to appropriate brainstem targets. We subjected rats to cervical level 1 (C1) lesions and combinatorial treatments to elicit axonal bridging into and beyond lesion sites. Lentiviral vectors expressing neurotrophin-3 (NT-3) were then injected into an appropriate brainstem target, the nucleus gracilis, and an inappropriate target, the reticular formation. NT-3 expression in the correct target led to reinnervation of the nucleus gracilis in a dose-related fashion, whereas NT-3 expression in the reticular formation led to mistargeting of regenerating axons. Axons regenerating into the nucleus gracilis formed axodendritic synapses containing rounded vesicles, reflective of pre-injury synaptic architecture. Thus, we report for the first time, to the best of our knowledge, the reinnervation of brainstem targets after SCI and an essential role for chemotropic axon guidance in target selection.",

author = "Alto, {Laura Taylor} and Havton, {Leif A.} and Conner, {James M.} and Hollis, {Edmund R.} and Armin Blesch and Tuszynski, {Mark H.}",

note = "Funding Information: We thank L. Ma and B. Sj{\"o}strand for technical assistance and J. Silver for helpful suggestions. This work was supported by the US National Institutes of Health (NS09881 and NS54883), the Veterans Administration, the International Spinal Research Trust, Wings for Life, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the Bernard and Anne Spitzer Charitable Trust.",

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AU - Blesch, Armin

AU - Tuszynski, Mark H.

N1 - Funding Information: We thank L. Ma and B. Sjöstrand for technical assistance and J. Silver for helpful suggestions. This work was supported by the US National Institutes of Health (NS09881 and NS54883), the Veterans Administration, the International Spinal Research Trust, Wings for Life, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the Bernard and Anne Spitzer Charitable Trust.

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N2 - A principal objective of spinal cord injury (SCI) research is the restoration of axonal connectivity to denervated targets. We tested the hypothesis that chemotropic mechanisms would guide regenerating spinal cord axons to appropriate brainstem targets. We subjected rats to cervical level 1 (C1) lesions and combinatorial treatments to elicit axonal bridging into and beyond lesion sites. Lentiviral vectors expressing neurotrophin-3 (NT-3) were then injected into an appropriate brainstem target, the nucleus gracilis, and an inappropriate target, the reticular formation. NT-3 expression in the correct target led to reinnervation of the nucleus gracilis in a dose-related fashion, whereas NT-3 expression in the reticular formation led to mistargeting of regenerating axons. Axons regenerating into the nucleus gracilis formed axodendritic synapses containing rounded vesicles, reflective of pre-injury synaptic architecture. Thus, we report for the first time, to the best of our knowledge, the reinnervation of brainstem targets after SCI and an essential role for chemotropic axon guidance in target selection.

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Chemotropic guidance facilitates axonal regeneration and synapse formation after spinal cord injury

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