Roles of BDNF in striatal neurons and relevance to Huntington's disease

描述（由申请人提供）：纹状体是基底神经节的最大组成部分，其变性是与亨廷顿病（HD）相关的运动功能障碍的原因，亨廷顿病是一种显性遗传性神经变性疾病，由亨廷顿（htt）蛋白N末端的聚谷氨酰胺束扩张引起。此外，它还与几种发育障碍有关。纹状体神经元绝大多数是中等大小的多刺神经元（MSN），其余是中间神经元。MSN分为两个群体：在间接途径中表达多巴胺受体D2（DRD2）的群体和在直接途径中表达多巴胺受体D1a（DRD1a）的群体。研究表明，MSNs出生于外侧神经节隆起（LGE）;然而，MSNs的进一步发育是如何调节的仍然是未知的。目前还不清楚普遍表达的htt的突变如何导致纹状体中的选择性和严重的神经元损失，以及为什么DRD2 MSN是HD患者纹状体中受影响最严重的细胞。我们假设顺行转运的脑源性神经营养因子（BDNF）和神经营养因子-3（NT3）控制新生MSN的存活和树突状分支。我们进一步假设，局部合成的突变htt树突在HD发病机制中起着关键作用，并在MSN中的TrkB（BDNF的受体）的差异表达有助于HD的选择性变性。这些假设是基于我们以前研究的有力证据。该研究项目有四个具体目标。具体目的1是调查是否BDNF和NT3转运顺行从黑质纹状体多巴胺能神经元支持新生MSN的生存，通过删除多巴胺能神经元中的BDNF或Nt3基因。具体目标2是通过使用培养的纹状体神经元和其中TrkB基因在DRD2表达细胞中缺失的突变小鼠来确定BDNF是否是DRD2 MSN的树突状分支的发展所需的。具体目标3是调查是否亨廷顿蛋白转录被运送到树突的本地翻译和树突合成的突变亨廷顿蛋白是否有助于HD的发病机制在培养的神经元。具体目的4是通过删除成年野生型和HD小鼠的DRD2表达细胞中的TrkB基因，检查DRD2 MSN中的优先TrkB表达是否有助于HD中的选择性变性。这项研究的结果将为纹状体发育的调控和HD的发病机制提供见解。

DESCRIPTION (provided by applicant): 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 (htt) protein. In addition, it has been implicated in several developmental disorders. 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. It also remains unclear how a mutation in the ubiquitously expressed htt causes selective and severe neuronal loss in the striatum and to a lesser extent in the cortex and why DRD2 MSNs are the most affected cells in the striata of HD patients. We hypothesize that anterogradely transported brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) control survival and dendritic arborization of newborn MSNs. We further hypothesize that local synthesis of mutant htt in dendrites plays a key role in the HD pathogenesis 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 four specific aims. Specific Aim 1 is to investigate whether BDNF and NT3 transported anterogradely from nigrostriatal dopaminergic neurons support the survival of newborn MSNs by deleting the BDNF or Nt3 gene in dopaminergic 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 investigate whether huntingtin transcripts are transported to dendrites for local translation and whether dendritic synthesis of mutant huntingtin contributes to the HD pathogenesis in cultured neurons. Specific Aim 4 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 pathogenesis of HD.