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.
