Developmental conditioning confers vulnerability in the adult and ageing nervous system
This thesis looks at the condition under which sympathetic neurons (SCG) develop in order to understand the causes of selective vulnerability during ageing and therefore shows how pre-treatment in vivo with NGF at a specific point during development affects SCG neurons. In summary, results show that following pre-treatment in vivo there is an increase in neuronal number, with differential effect on different subpopulations of neurons (MCA versus iris projecting neurons). MCA-projecting neurons (a vulnerable subpopulation of SCG neurons) increase in growth and innervation of specific target tissues following NGF pre-treatment in vivo, showing a maintained plasticity after termination of development and therefore a potential target site for future therapeutics. NGF pre-treatment in vivo also increases neuronal survival time throughout life, showing that the limited supply of NGF in real life prime neurons to a reduced potential. The results on survival also show a difference in the mode of action between the two major survival pathways (PI3-K and ERK), with PI3-K being the predominant in adult life and ERK acting mainly in early life. This shows a double survival mechanism which is plastic and capable of shifting predominance according to factors such as NGF stimuli and/or ageing. Furthermore if the NGF pre-treatment in vivo is applied after termination of development, neurons show plasticity by developing an 'addiction' or dependance to NGF pre-treatment termination results in death of the neurons. Preliminary results show increase in Akt activity which is downstream of PT3-K, and is activated in NGF-dependent survival of SCG neurons (Pierchala et aL, 2004). Biological consequences of Akt activation are survival, increase in cell number and growth, which are all characteristics relevant also to cancer-cell growth. Further preliminary results show an inhibition of GSK-3p pathways, which is downstream of Akt and is determinant for cytoskeletal rearrangement, glucose metabolism and cell survival regulation of GSK-3p has been widely studied in relation to Alzheimer's disease. In conclusions this research shows that sympathetic neurons are plastic and by priming mem with NGF, at a critical point during development, their survivability is increased. These results support the existence of a sensitive mechanism for adjusting neuronal capacity to resist cell death in response to neurotrophic factor deprivation.