RECOVERY MECHANISMS AFTER NEUROTRAUMA: PLASTICITY OF CNS CIRCUITS

Schwab, Martin E.

Brain Research Institute, University of Zurich and Dept. Biology, Swiss Federal Institute of Technology Zurich, Winterthurerstr.190, 8057 Zurich, Switzerland

Traditionally, circuits in the spinal cord have been viewed as static and therefore unable to respond in a plastic way to major injuries. Using anterograde and retrograde tracing, we recently found that corticospinal axons in the adult rat transected at T8 spontaneously sprout into the cervical spinal cord. These fibers contact interneurons, among them long propriospinal fibers projecting through the intact ventral funiculus to the lumbar spinal cord. Over time, these contacts stabilize, and the propriospinal neurons double their synapse number on lumbar motoneurons. The new circuit is functional as shown by the effects of a second lesion (pyramidotomy) on the partially recovered hind limb functions. – Sprouting and long distance regenerative growth of axons can be enhanced in the injured spinal cord of adult rats and adult macaques by intrathecal infusion of function-blocking antibodies against the neurite growth inhibitory CNS protein Nogo-A. Nogo-A antibodies reach   the entire spinal cord and brain after 7 days of intrathecal infusion; they bind to Nogo-A expressing oligodendrocytes and are internalized and degraded by these cells together with the endogenous Nogo-A. Sprouting and regeneration of corticospinal and 5-HT fibers occurs in rat and monkey spinal cords infused with anti-Nogo antibodies at a level much above that of control antibody-infused animals. Importantly, anatomical growth is accompanied by greatly improved functional recovery as reflected in a variety of sensory and motor tests. Malfunctions like pain and spasticity do not occur. These results show that the adult spinal cord is able to spontaneously form new circuits; this ability is greatly enhanced by suppression of the endogenous neurite growth inhibitor Nogo-A.