Chemotropic Mechanisms Could Regenerate Injured Spinal Cord Axons

A new study has demonstrated that regenerating axons can be guided to their correct targets and re-form connections after spinal cord injury (SCI).

Researchers at the University of California, San Diego (UCSD; USA) subjected rats to cervical level 1 (C1) lesions. They then used combinatorial treatments using lentiviral vectors expressing neurotrophin-3 (NT-3) to elicit axonal bridging into and beyond lesion sites by injected it into an appropriate brainstem target, the nucleus gracilis, and an inappropriate target, the reticular formation. The researchers found that 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 a mistargeting of regenerating axons. The regeneration required two other treatments at the same time: placing a cell bridge in the spinal cord injury site to support axon growth, and a conditioning stimulus to the injured neuron that "turned on” regeneration genes for new growth.

Using high-resolution imaging systems, the scientists showed that regenerating axons guided to the correct cell formed synapses that were precisely on target. The axons regenerating into the nucleus gracilis formed axodendritic synapses containing rounded vesicles, reflective of preinjury synaptic architecture; nonetheless, the connections were not electrically active. Further study revealed the likely reason for this: the regenerating axons were not covered in myelin, the insulating material of the nervous system; this will be the next step in the team's research. The study was published on August 2, 2009, in the advance online edition of the journal Nature Neuroscience.

"The ability to guide regenerating axons to a correct target after spinal cord injury has always been a point of crucial importance in contemplating translation of regeneration therapies to humans,” said senior author Mark Tuszynski, M.D., Ph.D., a professor of neurosciences at UCSD. "While our findings are very encouraging in this respect, they also highlight the complexity of restoring function in the injured spinal cord.”

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