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受体来调控神经元存活、分化和突触可塑性的关键参与者。BDNF-TrkB信号的缺乏和加剧与许多人类脑部疾病有关，分别以精神障碍和癫痫为代表。我们的长期目标是阐明控制BDNF产生和BDNF- trkb功能在正常和病理可塑性中的分子机制，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，BDNF的表达受到神经元活动变化的严格调控。虽然BDNF转录受到复杂的调控，但它不能解释神经元激活时BDNF蛋白和mRNA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树突运输的发现提出了一种有趣的可能性，即BDNF可能在响应神经元活动变化的树突/突触中局部翻译，这为控制长期突触调节提供了一种新方法。有趣的是，无论哪个启动子驱动BDNF转录，BDNF转录物的3‘端在两个可选的聚腺苷化位点进行加工，产生短或长3’非翻译区（3' utr）。最近的研究表明，虽然短的3'UTR限制了神经元体细胞中的BDNF mRNA，但长3'UTR将BDNF mRNA靶向到树突中，从而控制正常突触的发育和功能。我们的初步研究表明，神经元活动确实通过体细胞和树突室中不同的3' utr调节BDNF的翻译，并鉴定了靶向BDNF 3' utr的差异mirna。然而，控制BDNF翻译的分子机制和突触信号仍不清楚，这是开发控制BDNF- trkb功能的新方法的关键问题。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调控如何影响癫痫发生仍未被揭示。我们假设mirna对BDNF的翻译调控控制了BDNF在体细胞和树突状室的产生，从而调节了正常和病理可塑性。本研究主要关注以下问题：1)控制BDNF在体细胞和树突间室中翻译的分子机制和突触信号是什么？2) microrna如何参与BDNF的翻译调控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？

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.