The effect of prolonged axonal growth on the vulnerability of developing and adult motoneurons to cell death

Motoneurons are known to die following neonatal nerve injury. Prematurely enhancing transmitter release from developing nerve terminals induces motoneurons to become more resistant to subsequent nerve injury, whereas reducing transmitter release increases their susceptibility. In this Thesis I examine the relationship between the vulnerability of motoneurons to cell death and motoneuron phenotype, in developing and adult animals. In developing rats, increasing transmitter release from nerve terminals at birth resulted in the premature transition of motoneurons from a growth into a transmitting state. In contrast, decreasing transmitter release delayed this transition by maintaining motoneurons in a growth state, which increased their vulnerability to cell death. These results indicate that the target-induced up-regulation in transmitter release from developing nerve terminals, determines motoneurone phenotype and vulnerability to cell death. Adult motoneurons survive peripheral nerve injury and are able to withstand a period of growth associated with regeneration. However, even adult motoneurons may be more vulnerable to cell death when forced to grow for a prolonged period. The results of this Thesis show that extensive and prolonged growth caused by nerve injury in transgenic mice that over-express the growth-associated protein GAP-43, results in the progressive loss of motoneurons, possibly due to an increased vulnerability to excitotoxic cell death. Finally, in this Thesis I also examined the possibility that the extensive sprouting of motoneurons that initially survive in Amyotrophic Lateral Sclerosis may contribute to the progressive motoneuron degeneration that is a feature of this disease. The results show that inducing axonal growth during the presymptomatic phase of the disease in a transgenic mouse model of ALS increases the rate of disease progression. These results indicate that continued growth of motor axons renders both developing and adult motoneurons more vulnerable to cell death and implicates the excessive sprouting of motoneurons as a contributing factor in ALS