| dc.description | The adult mammalian central nervous system (CNS) exhibits a limited regenerative response to injury and disease. Attempts to promote or enhance recovery have been unsuccessful, largely because of the extensive cell loss that occurs following CNS insult. The rodent optic system provides a versatile model with which to study neuronal survival and axon plasticity. Specifically, retinal ganglion cells (RGCs) may be selectively labeled, and their death occurs in a predictable, time-dependent fashion following optic nerve (ON) transection. It is well established that the neural cell adhesion molecule (NCAM) and its polysialylated form (PSA-NCAM) influence plasticity, and recent studies indicate that these factors, which are both expressed constitutively in the retina and the superior colliculus (SC; RGC target tissue), mediate neuronal survival in culture. In this thesis, I investigated NCAM's and PSA's influences on RGC survival and axon plasticity. PSA-NCAM levels increase in the retina and SC following injury. Further evaluation of the retinorecipient layers of the partially denervated SC revealed that, in contrast to the normal colliculus, some intact CTB-traced RGC axons labeled from the ipsilateral eye co-localize with PSA-NCAM. Using adult NCAM -/- mice, I directly tested the potential influence of NCAM on RGC survival in vivo by quantifying RGCs. In NCAM -/- retinas, RGC densities are greater, RGC loss after axotomy is at least 2 days earlier and target tissue influences RGC survival, all in contrast to wild-type retinas. Furthermore, brain derived neurotrophic factor protein levels are greater in the uninjured adult NCAM -/- SC. I then investigated endogenous PSA's influence on the survival RGCs in developing, mature and pathophys lo logical conditions. RGC death occurs when PSA is removed from the surface of neonatal RGCs in vitro, and from neighbouring glial cells in the adult injured and uninjured retina in vivo. Collectively, these results implicate PSA-NCAM in RGC axon plasticity and demonstrate that endogenous NCAM and PSA promote CNS neuron survival in vivo. These findings have implications for the development of effective treatment strategies aimed at protecting and promoting growth of injured CNS neurons that would otherwise be destined to die in the eye, brain and spinal cord. | en_US |
