Human VGF Polymorphisms and Depression

描述（由申请人提供）：生长因子，特别是脑源性神经营养因子（BDNF），在神经系统中发挥关键作用，调节神经元发育和存活，轴突生长，突触发生和突触可塑性。BDNF信号调节抑郁行为，大量研究表明BDNF/TrkB通路在情境恐惧条件反射和空间记忆以及突触可塑性调节和长时程增强（LTP）诱导中起着额外的作用。这些功能可能依赖于BDNF在转录、翻译或翻译后水平调控的基因或基因产物，其中一些是通过激活转录因子CREB来实现的，CREB是许多不同物种中记忆的关键分子调节剂。然而，很少有神经营养因子和CREB下游的候选基因被确定，这些基因有助于记忆的形成。最近的研究表明，VGF是一种神经元分泌的蛋白和肽前体，可被神经营养因子BDNF、NGF和NT3快速诱导，在记忆形成中起作用。已知vgf衍生肽调节突触可塑性，生殖行为和能量平衡。最近的人类遗传SNP图谱发现了VGF多态性，该多态性导致VGF在氨基酸524后过早终止，消除了几种生物活性VGF肽和调节分泌所需的α -螺旋区域。本研究的初步数据表明，VGF c端肽具有抗抑郁作用，并调节海马神经元电兴奋性和海马切片突触可塑性，这与VGF敲除小鼠在空间记忆任务（如Morris水迷宫）和情境恐惧条件反射中的表现受损一致。在R21期的Aim 1中，我们将开发两种小鼠模型，将人类VGF等位基因敲入小鼠VGF位点，编码全长人类VGF（氨基酸1-615）或snp截断的VGF（氨基酸1-524）。在R33期的Aim 1中，我们将在这些小鼠模型中测试人类VGF的表达和功能，确定这种多态性的携带者是否易患抑郁症和认知障碍，就像那些BDNF表达和/或信号异常的人有记忆和行为障碍的风险一样。VGF敲入小鼠在空间和情境恐惧记忆任务以及抑郁和焦虑测试中的表现将被检验。总的来说，这些实验将研究VGF、VGF衍生肽和人类VGF基因的特定多态性在海马突触可塑性、抑郁和海马依赖记忆的调节中所起的作用。与公共卫生的相关性：控制认知和行为的分子和机制的表征将导致对大脑功能和记忆的更多了解，这两者都明显受到衰老，阿尔茨海默氏症或ALS等退行性疾病以及抑郁症等情绪障碍的影响。神经营养生长因子在调节大脑发育和功能的神经系统中起着至关重要的作用，但很少有候选基因被确定由神经营养因子诱导并有助于记忆形成和行为。对控制认知和行为的分子和机制的表征将导致对大脑功能和记忆的进一步了解，这两者都明显受到衰老、阿尔茨海默氏症或ALS等退行性疾病以及抑郁症等情绪障碍的影响。

DESCRIPTION (provided by applicant): Growth factors in general, and brain-derived neurotrophic factor (BDNF) in particular, play critical roles in the nervous system to regulate neuronal development and survival, axonal outgrowth, synaptogenesis, and synaptic plasticity. BDNF signaling modifies depressive behavior, and a large number of studies demonstrate additional roles for BDNF/TrkB pathways in contextual fear conditioning and spatial memory, as well as in the regulation of synaptic plasticity and the induction of long term potentiation (LTP). These functions likely depend on genes or gene products that BDNF regulates at the transcriptional, translational or post-translational levels, several via activation of the transcription factor CREB, a critical molecular regulator of memory in a number of different species. However, few candidate genes downstream of neurotrophins and CREB that contribute to memory formation have been identified. Recent studies suggest that VGF, a neuronal secreted protein and peptide precursor that is rapidly induced by the neurotrophins BDNF, NGF and NT3, plays a role in memory formation. VGF-derived peptides are known to regulate synaptic plasticity, reproductive behavior and energy balance. Recent human genetic SNP mapping has identified a VGF polymorphism that results in premature VGF termination after amino acid 524, eliminating several bioactive VGF peptides and an alpha-helical region required for regulated secretion. Preliminary data included in this proposal show that VGF C-terminal peptides have anti-depressant efficacy and also regulate hippocampal neuronal electrical excitability and synaptic plasticity in hippocampal slices, consistent with impaired performance of VGF knockout mice in spatial memory tasks (e.g. Morris water maze) and contextual fear conditioning. In Aim 1 of the R21 phase, we will develop two mouse models that knock human VGF alleles into the mouse Vgf locus, encoding either full length human VGF (amino acids 1-615) or SNP-truncated VGF (amino acids 1-524). In Aim 1 of the R33 phase, we will test expression and function of human VGF in these mouse models, determining whether carriers of this polymorphism could be predisposed to depression and impaired cognition, much as those with aberrant BDNF expression and/or signaling are at risk for memory and behavioral disorders. Performance of VGF knock-in mice will be examined in spatial and contextual fear memory tasks, and in depression and anxiety testing. Overall, the proposed experiments will investigate the roles that VGF, VGF-derived peptides, and a specific polymorphism in the human VGF gene, play in the regulation of hippocampal synaptic plasticity, depression, and hippocampal-dependent memory. Relevance to Public Health: Characterization of the molecules and mechanisms that control cognition and behavior will lead to increased understanding of brain function and memory, both of which are clearly impacted by aging, by degenerative diseases such as Alzheimer's or ALS, and by mood disorders such as depression. to Public Health: Neurotrophic growth factors play critical roles in the nervous system to regulate brain development and function, but few candidate genes have been identified that are induced by neurotrophins and contribute to memory formation and behavior. Characterization of the molecules and mechanisms that control cognition and behavior will lead to increased understanding of brain function and memory, both of which are clearly impacted by aging, by degenerative diseases such as Alzheimer's or ALS, and by mood disorders such as depression.