Structural and functional regeneration after spinal cord injury

In humans, like in any mammalian species, spinal cord injury represents a devastating condition, leading to permanent disability. Despite the tremendous number of investigations that have been conducted using mammalian model systems, therapeutic approaches have had limited success to date. An alternative strategy in the search for treatment of spinal cord lesions is provided by regeneration-competent vertebrates, including teleost fish. These animals are capable of spontaneous structural and functional recovery after spinal cord injury. We have established the weakly electric fish Apteronotus leptorhynchus as an excellent model system of such a regenerative process. As part of this research, we have identified key processes that underlie the enormous regenerative potential of this species, including the elimination of injured cells through apoptotic cell death, and the replacement of neurons lost to injury by newly generated nerve cells. Most remarkably, by employing a novel behavioral paradigm developed in our laboratory, we have been able to demonstrate that this structural regeneration leads to full recovery of the behavioral function generated by the spinal motoneurons within a few weeks after the injury.

Overview of some of the major processes involved in spinal cord regeneration in A. leptorhynchus. Amputation of the caudal part of the tail at the level indicated by the dotted line completely severs the spinal cord. Soon after the injury, numerous apoptotic active caspase‑3‑positive cells can be observed close to the lesion site. These high levels of apoptosis give way to cell proliferation, which increases rapidly and peaks 10 days after the injury. The massive levels of cell proliferation lead to the formation of an undifferentiated blastema at the tip of the regenerating tail, including the spinal cord. Subsequently, the caudal tip of the spinal cord, starting with the ependymal tube, extends into this blastema. The extension of the regenerating spinal cord appears to be supported by cell proliferation both at its caudal end and within the more rostral parenchyma. Differentiation of the newly generated cells into neurons and glia proceeds in a rostro‑caudal direction. (From: Sîrbulescu and Zupanc, 2011.)

Computer simulation of spinal cord regeneration dynamics. In addition to cellular details of the structural regeneration process, the recovery of the electric organ discharge is shown. (From: Sîrbulescu et al., 2009.)

Selected Publications:

Sîrbulescu, R.F., Ilieş, I., Zupanc, G.K.H.: Structural and functional regeneration after spinal cord injury in the weakly electric teleost fish, Apteronotus leptorhynchus. Journal of Comparative Physiology A 195, 699-714 (2009), doi:10.1007/s00359-009-0445-4

Sîrbulescu, R.F., Zupanc, G.K.H.: Dynamics of caspase-3-mediated apoptosis during spinal cord regeneration in the teleost fish, Apteronotus leptorhynchus. Brain Research 1304, 14-25 (2009), doi:10.1016/j.brainres.2009.09.071

Sîrbulescu, R.F., Zupanc, G.K.H.: Effect of temperature on spinal cord regeneration in the weakly electric fish, Apteronotus leptorhynchus. Journal of Comparative Physiology A 196, 359-368 (2010), doi:10.1007/s00359-010-0521-9

Sîrbulescu, R.F., Zupanc, G.K.H.: Inhibition of caspase-3-mediated apoptosis improves spinal cord repair in a regeneration-competent vertebrate system. Neuroscience 171, 599-612 (2010), doi:10.1016/j.neuroscience.2010.09.002

Sîrbulescu, R.F., Zupanc, G.K.H.: Spinal cord repair in regeneration-competent vertebrates: adult teleost fish as a model system. Brain Research Reviews 67, 73-93 (2011), doi:10.1016/j.brainresrev.2010.11.001