Role of BDNF-TRKB signaling in development and maintenance of the basal ganglia
Thesis (Ph.D.)--Georgetown University, 2010.; Includes bibliographical references.; Text (Electronic thesis) in PDF format. The basal ganglia consist of subcortical nuclei involved in integration of motor, associative, and cognitive behaviors. Recent studies have shown that different neuronal populations of the basal ganglia are dependent on trophic support for their development, survival, and proper function. Increased attention has been given to brain derived neurotrophic factor (BDNF) and its function in normal and pathological conditions. Here we investigate the role of BDNF-TrkB signaling in developing striatum, a major part of the basal ganglia responsible for movement control. We demonstrate that BDNF controls striatal size by promoting survival of newborn medium-sized spiny neurons (MSNs). Deletion of the gene for BDNF receptor, TrkB in striatal progenitors led to loss of 50% MSNs. The loss mainly resulted from increased apoptosis of newborn MSNs within the lateral ganglionic eminence (LGE). Among MSNs those expressing the dopamine receptor D2 were most affected, due to preferential TrkB expression in these cells. We proposed that BDNF is anterogradely transported from the dopaminergic neurons residing in the substantia nigra pars compacta (SNc). Indeed, a similar phenotype was observed when BDNF expression was ablated in dopaminergic neurons of the SNc that project to the LGE and striatum during embryogenesis. These results establish a novel mechanism for coordinating development of two connected nuclei in the basal ganglia.; Several studies have linked reduced levels of BDNF in the SNc to the pathogenesis of Parkinson's disease (PD). We show that BDNF-TrkB signaling is important for survival of nigrostriatal dopaminergic (DA) neurons in aging brains. A significant loss of DA neurons occurred at 12-24 months of age in the SNc of TrkB hypomorphic mice in which the TrkB receptor is expressed at less than 25% of the normal amount. The neuronal loss was accompanied by a decrease in dopaminergic axonal terminals in the striatum and by gliosis in both the SNc and striatum. Furthermore, nigrostriatal DA neurons in the TrkB mutant showed hypersensitivity to a neurotoxin-induced cell death. These data suggest that BDNF-TrkB signaling plays a role in the long-term maintenance of the nigrostriatal system and that its deficiency may contribute to the progression of PD.
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