SCIRP 2012 Investigator Vignette
Title: Improving Transmission in Damaged Spinal Cord to Promote Recovery of Function After Spinal Cord Injury
Investigator: Victor Arvanian, PhD, DSi; Northport Veterans Affairs Medical Center
So the outline of this grant is that the most of spinal cord injuries are incomplete anatomically. It means that there are lots of fibers remaining after the injury, the intact fibers. However, almost all injuries are complete functionally; meaning that below the level of injury there is no sensation and motor function below this level of injury.
In order to understand why these surviving fibers cannot mediate better recovery, we did electro-physiological experiments in which we evaluated physiological conditions of these fibers. And we found that immediately after the injury these surviving fibers can transmit to motor neurons. However, there is a pronounced reduction in transmission through the surviving fibers after a couple days after the injury. And what is important is that initiation of this physiological and behavioral deficit, coincided with the time whether elevation of scar-related molecules, which are chondroitin sulfate proteoglycans, so called CSPGs, in tissues was maximum.
NG2 belongs to the family of chondroitin sulfate proteoglycans that are upregulated after spinal cord injury (SCI) and are major inhibitory factors restricting the growth of fibers after SCI. Neutralization of NG2’s inhibitory effect on axon growth by anti-NG2 monoclonal antibodies (NG2-Ab) has been reported. In addition, recent studies show that exogenous NG2 induces a block of axonal conduction. In this study, we demonstrate that acute intraspinal injections of NG2-Ab prevented an acute block of conduction by NG2. Chronic intrathecal infusion of NG2-Ab improved the following deficits induced by chronic midthoracic lateral hemisection (HX) injury: (1) synaptic transmission to lumbar motoneurons, (2) retrograde transport of fluororuby anatomical tracer from L5 to L1, and (3) locomotor function assessed by automated CatWalk gait analysis. We collected data in an attempt to understand the cellular and molecular mechanisms underlying the NG2-Ab-induced improvement of synaptic transmission in HX-injured spinal cord. These data showed the following: (1) that chronic NG2-Ab infusion improved conduction and axonal excitability in chronically HX-injured rats, (2) that antibody treatment increased the density of serotonergic axons with ventral regions of spinal segments L1-L5, (3) and that NG2-positive processes contact nodes of Ranvier within the nodal gap at the location of nodal Na channels, which are known to be critical for propagation of action potentials along axons. Together, these results demonstrate that treatment with NG2-Ab partially improves both synaptic and anatomical plasticity in damaged spinal cord and promotes functional recovery after HX SCI. Neutralizing antibodies against NG2 may be an excellent way to promote axonal conduction after SCI.