Regulation of the Development of Mesencephalic Dopaminergic Systems by the Selective Expression of Glial Cell Line-Derived Neurotrophic Factor in Their Targets

Abstract

Glial cell line-derived neurotrophic factor (GDNF) has been shown to protect and restore dopamine (DA) neurons in injury models and is being evaluated for the treatment of Parkinson's disease. Nevertheless, little is known of its physiological role. We have shown that GDNF suppresses apoptosis in DA neurons of the substantia nigra (SN) postnatally both in vitro and during their first phase of natural cell death in vivo. Furthermore, intrastriatal injection of neutralizing antibodies augments cell death, suggesting that endogenous GDNF plays a role as a target-derived factor. Such a role would predict that overexpression of GDNF in striatum would increase the surviving number of SN DA neurons. To test this hypothesis, we used the tetracycline-dependent transcription activator (tTA)/tTA-responsive promoter system to create mice that overexpress GDNF selectively in the striatum, cortex, and hippocampus. These mice demonstrate an increased number of SN DA neurons after the first phase of natural cell death. However, this increase does not persist into adulthood. As adults, these mice also do not have increased dopaminergic innervation of the striatum. They do, however, demonstrate increased numbers of ventral tegmental area (VTA) neurons and increased innervation of the cortex. This morphologic phenotype is associated with an increased locomotor response to amphetamine. We conclude that striatal GDNF is necessary and sufficient to regulate the number of SN DA neurons surviving the first phase of natural cell death, but it is not sufficient to increase their final adult number. GDNF in VTA targets, however, is sufficient to regulate the adult number of DA neurons.

Behavioral genetic contributions to the study of addiction-related amphetamine effects

“…These data suggest that the decreased BDNF expression that has been observed in Huntington's disease patients may contribute to exacerbation of dopamine-related motor disturbances characteristic of this disease (Pineda et al, 2005). Finally, glial derived neurotrophic factor overexpression transgenic mice exhibited enhanced sensitivity to amphetamine-induced locomotor stimulation (Kholodilov et al, 2004). This may have been related to the increased number of ventral tegmental area neurons surviving into adulthood in these mice.…”

GDNF and protection of adult central catecholaminergic neurons

“…In support of this view is the fact that blocking GDNF function by injection of neutralizing antibodies enhances cell death during the first period of naturally occurring apoptosis in the SN (Oo et al 2003). In addition, striatal GDNF expression leads to a transient increase in SN cell number and a permanent augmentation in the number of VTA neurons (Kholodilov et al 2004). …”

Effects of Prenatal and Neonatal Exposure to Bisphenol A on the Development of the Central Nervous System

“…and brain-derived neurotrophic factor (BDNF) in mesencephalic cultures with a conditioned medium; this resulted in an increase in the number of dopaminergic neurons. GDNF is an important neurotrophic factor for the regulation of the development and for the survival of the midbrain dopaminergic neurons (Lin et al, 1993;Kholodilov et al, 2004). Shh and fibroblast growth factor-8 (FGF-8) have been reported to direct the differentiation of progenitor cells into midbrain dopaminergic neurons (Lee et al, 2000).…”