Cellular Delivery of Neurotrophin-3 Promotes Corticospinal Axonal Growth and Partial Functional Recovery after Spinal Cord Injury

Abstract

The injured adult mammalian spinal cord shows little spontaneous recovery after injury. In the present study, the contribution of projections in the dorsal half of the spinal cord to functional loss after adult spinal cord injury was examined, together with the effects of transgenic cellular delivery of neurotrophin-3 (NT-3) on morphological and functional disturbances. Adult rats underwent bilateral dorsal column spinal cord lesions that remove the dorsal corticospinal projections or underwent more extensive resections of the entire dorsal spinal cord bilaterally that remove corticospinal, rubrospinal, and cerulospinal projections. Long-lasting functional deficits were observed on a motor grid task requiring detailed integration of sensorimotor skills, but only in animals with dorsal hemisection lesions as opposed to dorsal column lesions. Syngenic primary rat fibroblasts genetically modified to produce NT-3 were then grafted to acute spinal cord dorsal hemisection lesion cavities. Up to 3 months later, significant partial functional recovery occurred in NT-3-grafted animals together with a significant increase in corticospinal axon growth at and distal to the injury site. These findings indicate that (1) several spinal pathways contribute to loss of motor function after spinal cord injury, (2) NT-3 is a neurotrophic factor for the injured corticospinal projection, and (3) functional deficits are partially ameliorated by local cellular delivery of NT-3. Lesions of the corticospinal projection may be necessary, but insufficient in isolation, to cause sensorimotor dysfunction after spinal cord injury in the rat.