Neurotrophin-3 ExpressedIn SituInduces Axonal Plasticity in the Adult Injured Spinal Cord

Abstract

The mammalian CNS lacks the ability to effectively compensate for injury by the regeneration of damaged axons or axonal plasticity of intact axons. However, reports suggest that molecular or cellular manipulations can induce compensatory processes that could support regeneration or plasticity after trauma. We tested whether local, sustained release of the neurotrophic factor neurotrophin-3 (NT-3) would support axonal plasticity in the spinal cord distal to the site of injury in rats. The corticospinal tract (CST) was cut unilaterally at the level of the medulla. This avoided excessive inflammation, secondary cell death, vascular disruption, and the release of inhibitory molecules in the lumbar spinal cord. A replication-defective adenoviral vector (Adv) carrying the NT-3 gene (Adv.EFalpha-NT3) was delivered to the spinal motoneurons by retrograde transport through the sciatic nerve. Retrograde transport of the adenoviral vectors avoided the inflammatory response that would be associated with direct injection into the spinal cord. Transduction of spinal motoneurons with Adv.EFalpha-NT3 resulted in a significant increase in the concentration of NT-3 in the L3-L6 region of the spinal cord for up to 3 weeks. In animals with a CST lesion, this local expression of NT-3 induced growth of axons from the intact CST across the midline to the denervated side. If the CST remained intact, overexpression of NT-3 did not lead to an increase in the number of axons crossing the midline. These data demonstrate that local, sustained expression of NT-3 will support axonal plasticity of intact CST axons after trauma-induced denervation.

Plasticity After Spinal Cord Injury: Relevance to Recovery and Approaches to Facilitate It

“…In a subsequent study, infusion of NT-3 into the cervical or thoracic spinal cords after incomplete lesions of corticospinal tract axons bilaterally in the pyramids reduced collateral sprouting [108]. Zhou et al [109] lesioned corticospinal tract axons unilaterally in the pyramids and induced retrograde expression of NT-3 within lumbar motor neurons on the denervated side. The expression of NT-3 induced collateral sprouting from the uninjured corticospinal tract axons into the denervated contralateral spinal cord.…”

“…The expression of NT-3 induced collateral sprouting from the uninjured corticospinal tract axons into the denervated contralateral spinal cord. Contralateral sprouting was only observed after acute injury [109,110] and could be enhanced with secondary application of BDNF or glial cell line-derived neurotrophic factor adenovirus within the motor cortex of the lesioned pathway [111]. Adeno-associated virus also can be retrogradely transported into the spinal cord.…”

Prenatal Exposure to Elevated NT3 Disrupts Synaptic Selectivity in the Spinal Cord

“…NT3 is a member of the nerve growth factor-related family of neurotrophins that regulate neuronal survival, differentiation, and axonal growth (Hory-Lee et al, 1993;Lindsay, 1996;Coppola et al, 2001;Zhou et al, 2003). For proprioceptive sensory neurons supplying muscles, NT3 is best known for its key role in determining the number of these neurons that survive the period of naturally occurring cell death.…”

Genetic modification of mesenchymal stem cells in spinal cord injury repair strategies

“…At 5 weeks after transplantation of modified effect in a cellular SCI model of rat spinal cord neurons (17). Moreover, transduction of spinal motoneurons with adenoviral vector (Adv) carrying the NT-3 gene induced growth of axons from the intact corticospinal tract (CST) across the midline to the denervated side in animals with a CST lesion (18).…”