Neurotrophic factors and neuronal plasticity

Abstract: The neurotrophic factors were originally discovered because of their ability to rescue neurons during a period of naturally occurring programmed cell death. This gave rise to the neurotrophic factor hypothesis which states that specific target-derived factors protect and support subpopulations of innervating neurons, thereby regulating the pattern and quantity of innervation properly for each target tissue. In recent years it has been realized that neurotrophic factors can also induce or modulate neuronal plasticity, such as the synaptic potentiation, synaptogenesis and neuropil growth thought to be the molecular basis of many forms of learning and memory. This thesis shows that brain-derived neurotrophic factor (BDNF) has many previously unknown functions in the adult brain. A direct involvement in memory acquisition is shown by the fact that lowering BDNF levels causes a spatial learning defect. Moreover, it is shown that BDNF is required for the proper development of the dentate gyrus and for the survival or proper maturation of adult neural stem cells. A direct action of BDNF on Reelin, a protein responsible for inducing normal cortical lamination, is demonstrated and shown to cause a reeler-like phenotype in BDNF-overexpressing mice. Finally, the transcriptional program in response to glial cell line-derived neurotrophic factor (GDNF) is explored, revealing that this neurotrophic factor, too, affects neuronal plasticity. Several classes of genes responded to GDNF, including a large set of genes involved in cellular morphology and neurite growth, several genes related to translation and Sox10, itself a regulator of Ret (a GDNF receptor). In conclusion, this thesis demonstrates a variety of effects of the neurotrophic factors GDNF and BDNF in the postnatal nervous system, and begins to suggest that the most important functions of these proteins may not be as survival factors but as plasticity modulators.