Targeted gene transfer in the developing central nervous system using viral vectors

Sammanfattning: Dopamine (DA) is a neurotransmitter that plays a fundamental role in many aspects of normal brain function. The majority of DA neurons in the brain reside in one region ? the midbrain ? and project axonal connections to specific areas. One of the main target regions of the DA system is the striatum. This connection is known as the nigrostriatal pathway. During early development, a particular population of midbrain DA neurons project their axons towards the striatum, and molecular cues along the nigrostriatal pathway guide the fibers to their final destination. Very little is known about the cues that are responsible for this DA axon guidance. One potential candidate for the axon guidance of the DA fibers of the nigrostriatal pathway is glial cell line-derived neurotrophic factor (GDNF). GDNF is expressed in the developing striatum during the period when the DA fibers are innervating this structure, raising the possibility that it may be a target molecule for DA axons at the end of the pathway. Further strengthening this suggestion is the fact that GDNF is robustly expressed in regions of the striatum that the DA fibers preferentially innervate upon entering the striatum. In the present thesis, I have attempted to investigate the role of GDNF as a target molecule for the DA fiber innervation of the striatum during development. This work has primarily involved the development and characterization of surgical procedures that allow gene transfer into the nigrostriatal system in vivo during different periods of pre- and postnatal development. The gene transfer was mediated by different kinds of recombinant viral vectors. The results provide further evidence supporting the involvement of GDNF in DA fiber innervation of the developing striatum, but more importantly the gene transfer procedures used in this thesis represent future opportunities for wider in vivo applications.