Campioni-Noack, M.; (2005) Developmental conditioning confers vulnerability in the adult and ageing nervous system. Doctoral thesis , University of London.

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Abstract

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.

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