Translation regulation of BDNF in brain function

描述（由申请人提供）：脑源性神经营养因子（BDNF）是通过激活TrkB受体控制神经元存活、分化和突触可塑性的关键因素。BDNF-TrkB信号传导的缺乏以及恶化与许多人脑疾病有关，分别以精神障碍和癫痫为代表。我们的长期目标是阐明在正常和病理可塑性中控制BDNF产生和BDNF-TrkB功能的分子机制，这对开发针对涉及BDNF功能障碍的疾病的新策略具有重要影响。由于BDNF的多效性功能，BDNF的表达响应于神经元活性变化而受到严格调节。虽然BDNF的转录受到复杂的调控，但它不能解释BDNF蛋白和mRNA在神经元激活后的不同时间分布以及可扩散的BDNF蛋白如何实现局部和突触选择性调节。神经元活动刺激的BDNF mRNA树突转运的发现提出了一个有趣的可能性，BDNF可能是局部翻译树突/突触响应神经元活动的变化，这提供了一种新的手段来控制长期的突触调制。有趣的是，无论哪个启动子驱动BDNF转录，BDNF转录物的3 '端在两个可选的多聚腺苷酸化位点处被加工，产生短或长的3'非翻译区（3 'UTR）。最近的研究表明，虽然短的3 'UTR限制了神经元索马中的BDNF mRNA，但长的3' UTR将BDNF mRNA靶向树突，树突反过来又控制正常的突触发育和功能。我们的初步研究表明，神经元活动确实通过不同的3 'UTR在体细胞和树突隔室调节BDNF的翻译，并确定了差异靶向BDNF 3' UTR的miRNA。然而，控制BDNF翻译的分子机制和突触信号仍然是难以捉摸的，这是开发新的方法来控制BDNF-TrkB功能的关键问题。此外，尽管我们最近的报告显示BDNF长3 'UTR在正常突触发育中起重要作用，但3' UTR介导的BDNF调节如何影响癫痫发生仍然没有被发现。我们推测，BDNF的翻译调控的miRNA管理BDNF的生产在体细胞和树突状细胞的车厢，以调节正常和病理可塑性。本研究主要探讨以下几个问题：1）在体细胞和树突细胞中，控制BDNF翻译的分子机制和突触信号是什么？2)microRNA如何参与BDNF的翻译调节以适应神经元活动的变化？3)活动依赖性BDNF翻译在癫痫发生中的功能影响是什么？ 公共卫生相关性：BDNF的准确表达对于控制正常的神经元发育和功能至关重要。BDNF表达的缺乏或恶化都可能导致脑疾病。因此，了解BDNF的精确调节是开发针对许多脑部疾病的策略的关键先决条件。阐明BDNF在神经元活性变化后在体细胞和树突细胞中翻译的分子机制将为BDNF-TrkB功能的空间和时间控制提供概念上的突破。成功完成拟议的研究将大大推进我们的知识，关于BDNF的翻译是如何调节神经元和突触激活，这反过来又控制正常以及病理可塑性。此外，这些研究将为控制神经元活性依赖性翻译的基本规则提供重要见解，特别是通过microRNA介导的机制，这是理解脑神经元中许多mRNA调控的及时和重要问题，超出了BDNF功能。

DESCRIPTION (provided by applicant): Brain derived neurotrophic factor (BDNF) is a key player that governs neuronal survival, differentiation and synaptic plasticity via activation of the TrkB receptor. Deficiency as well as exacerbation of BDNF-TrkB signaling is implicated in many human brain disorders, represented by mental impairment and epilepsy respectively. Our long-term goal is to elucidate molecular mechanisms that control BDNF production and BDNF-TrkB function in normal and pathological plasticity, which has important impact in developing novel strategies against diseases that involve BDNF dysfunction. Due to the pleiotropic functions of BDNF, expression of BDNF is tightly regulated in response to neuronal activity changes. Although BDNF transcription is subjected to sophisticated regulation, it could not explain the distinct temporal profiles of BDNF protein and mRNA upon neuronal activation and how the diffusible BDNF protein achieves local and synapse-selective modulation. The discovery of neuronal activity-stimulated dendritic transport of BDNF mRNA raises an intriguing possibility that BDNF may be locally translated in dendrites/synapse in response to neuronal activity changes, which offers a novel means to control long term synaptic modulation. Interestingly, regardless which promoter drives BDNF transcription, the 3'end of the BDNF transcript is processed at two alternative poly- adenylation sites, generating either a short or a long 3' untranslated region (3'UTR). The most recent studies revealed that while the short 3'UTR restricts BDNF mRNA in the neuronal soma, the long 3'UTR targets the BDNF mRNA into dendrites, which in turn governs normal synapse development and function. Our preliminary studies suggest that neuronal activity indeed regulates BDNF translation via the distinct 3'UTRs in the somatal and dendritic compartments, and identified miRNAs that differentilaly target the BDNF 3'UTRs. However, molecular mechanisms and synaptic signals controlling BDNF translation still remain elusive, which is a key issue for developing novel means to control BDNF-TrkB function. Moreover, despite the essential role of the BDNF long 3'UTR in normal synapse development as shown in our recent report, how 3'UTR-mediated regulation of BDNF may impact epileptogenesis remains uncovered. We hypothesize that translation regulation of BDNF by miRNAs governs BDNF production in the somatal and dendritic compartments to modulate normal and pathological plasticity. This proposal focuses on the following questions: 1) What are the molecular mechanisms and synaptic signals that control BDNF translation in the somatal and dendritic compartments? 2) How are microRNAs involved in translation regulation of BDNF to accommodate neuronal activity changes? 3) What are the functional impacts of activity-dependent BDNF translation in epileptogenesis? PUBLIC HEALTH RELEVANCE: Accurate expression of BDNF is crucial for governing normal neuronal development and function. Either deficiency or exacerbation of BDNF expression can contribute to brain disorders. Thus, understanding the precise regulation of BDNF is a critical prerequisite for developing strategies against many brain diseases. Elucidating molecular mechanisms that underlie BDNF translation in the somatal and dendritic compartments upon neuronal activity changes will provide a conceptual breakthrough for the spatial and temporal control of BDNF-TrkB function. Successful completion of the proposed studies will greatly advance our knowledge regarding how BDNF translation is regulated upon neuronal and synaptic activation, which in turn governs normal as well as pathological plasticity. Moreover, these studies will provide important insights for the fundamental rules that control neuronal activity-dependent translation, especially by microRNA- mediated mechanisms, a timely and important issue in understanding the regulation of many mRNAs in brain neurons, beyond BDNF function.