Generation and Analysis of Conditional Pre-Clinical Model Mutants for BNDF and GDNF Receptors

Parkinson's disease results largely from the degeneration of dopamincergic neurons in the substantia nigra pars compacta. The reason for the successive death of these neurons is not known so far. Experiments on mature neurons in culture and on animals with brain injuries support the notion that neurotrophic factors are important for survival of neurons in the adult brain. Pharmacological and in vitro studies have shown promising effects on survival of dopaminergic neurones, especially for the neurotrophic factors BDNF and GDNF. However, the endogenous survival factors for dopaminergic neurons during postnatal development and in adulthood have not been determined. Knowledge about the endogenous neurotrophic factors for dopaminergic neurons will allow to evaluate and to improve potential neurotrophic therapies for the treatment of Parkinson's disease. To address this important question we will disrupt expression of the receptor for BDNF, TrkB, and for the GDNF-family of neurotrophic factors (GDNF, NRTN, PSPN and ARTN), c-Ret, in an in vivo animal model. We will use the Cre-Lox conditional mutagenesis system combined with the inducible tet-on system, to limit the deficiency of TrkB and c-Ret in space (dopaminergic and dopamine responsive neurons) and time (postnatal stages). At different time points after induction of the recombination event, animals will be analysed for the integrity of the nigrostriatal system. We expect that in the absence of TrkB and c-Ret, dopaminergic neurons will show defects ranging from loss of dopaminergic cell traits, to atrophy, or cell death. These experiments will, for the first time, test if BDNF and GDNF-family of growth factors are required for dopaminergic neurons in vivo, or whether other trophic factors and their receptors play more important roles. The newly generated transgenic animals will also allow us to inducibly delete or overexpress genes specifically in dopaminergic neurons and test their importance concerning survival and function.