8.1 Neurotrophism and Neurotrophic Factors Neurotrophic factors (NTFs) are small natural proteins necessary for the development and survival of nerve cells as well as for the maintenance of their morphological and functional phenotype. The 'neurotrophic hypothesis' enunciates that the establishment and maintenance of neuronal networks require the release at the target structures of NTFs, which are taken up by the nerve terminals and retrogradely transported to the soma of the projecting neurons. On reaching the nucleus, NTFs induce a gene programme that promotes neuronal survival and maintenance of phenotype. Although the existence of 'chemotactic' influences between the growth cones of axons and their targets had already been postulated by Cajal's group, 1 the modern concept of neurotrophism is based on the work of Hamburguer and Levi-Montalcini 2 who reported that the phenomenon of naturally occurring RSC Drug Discovery Series No. 6 Animal Models for Neurodegenerative Disease Edited by Jesus Avila, Jose J. Lucas and Felix Hernandez r Royal Society of Chemistry 2011 Published by the Royal Society of Chemistry, www.rsc.org 162 cell death observed during development was dependent on the target where these dying neurons were projecting. Removing a prospective target early in development could dramatically increase neuronal loss. In the absence of target, the number of initially existing neurons did not change, indicating that the target influences survival and not the number of neurons generated. These seminal observations suggested that cells acting as a target of developing neurons produce limited amount of specific molecules which are required for their survival. The first molecule identified with these specific characteristics was the nerve growth factor (NGF). 3,4 As indicated above, the current concept of NTF applies not only to molecules regulating neuronal number during development but also to agents necessary for the maintenance of neuronal populations in adulthood. 5,6