The striatum is the largest component of the basal ganglia, and its degeneration is the cause for motor dysfunction associated with Huntington s disease (HD), a dominantly inherited neurodegenerative disorder caused by the expansion of a polyglutamine tract at the N-terminus of the huntingtin protein. It is important to understand both normal striatal development and HD pathogenesis in order to develop treatments, such as cell replacement therapy, for HD. The vast majority of striatal neurons are medium-sized spiny neurons (MSNs) with the rest being interneurons. MSNs are divided into two populations: those expressing the dopamine receptor D2 (DRD2) in the indirect pathway and those expressing the dopamine receptor D1a (DRD1a) in the direct pathway. Studies have demonstrated that MSNs are born in the lateral ganglionic eminence (LGE); however, it remains largely unknown how the further development of MSNs is regulated. MSNs of the indirect pathway are most affected in HD; but it is unclear why these neurons are selectively degenerated when mutant huntingtin is expressed throughout the brain. We hypothesize that brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) from nigrostriatal dopaminergic (DA) neurons support the survival of newborn MSNs within the LGE and thus control the striatal size during embryogenesis. We further hypothesize that BDNF is essential for the dendritic arborization and maintenance of MSNs in the indirect pathway and that differential expression of TrkB (the receptor for BDNF) in MSNs contributes to selective degeneration in HD. These hypotheses are based on strong evidence from our previous studies. This research project has three specific aims.
Specific Aim 1 is to investigate whether BDNF and NT3 transported anterogradely from nigrostriatal DA neurons support the survival of newborn MSNs by deleting the Bdnf or Nt3 gene in DA neurons.
Specific Aim 2 is to determine whether BDNF is required for the development of dendritic arborization of DRD2 MSNs by using cultured striatal neurons and mutant mice where the TrkB gene is deleted in DRD2-expressing cells.
Specific Aim 3 is to examine whether the preferential TrkB expression in DRD2 MSNs contributes to selective degeneration in HD by deleting the TrkB gene in DRD2-expressing cells of adult wild-type and HD mice. Results from this proposed research will provide insights into the regulation of striatal development and the mechanism underlying selective degeneration of HD.
The striatum is the largest component of the basal ganglia and is associated with several neurological disorders, including Huntington?s disease (HD). Findings from this proposed research will provide important information as to HD pathogenesis and cell replacement therapy for striatum-based diseases.
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