Human VGF Polymorphisms and Depression

描述(申请人提供)：一般而言，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，调节神经元的发育和存活、轴突生长、突触发生和突触可塑性。BDNF信号可以改变抑郁行为，大量研究表明BDNF/TrkB通路在情景恐惧条件反射、空间记忆、突触可塑性的调节和长时程增强(LTP)的诱导中具有额外的作用。这些功能可能依赖于BDNF在转录、翻译或翻译后水平上调节的基因或基因产物，其中一些是通过激活转录因子CREB来调节的，CREB是许多不同物种记忆的关键分子调节因子。然而，神经营养因子和CREB下游与记忆形成有关的候选基因很少被发现。最近的研究表明，VGF是一种神经分泌蛋白和多肽前体，由神经营养因子BDNF、NGF和NT3快速诱导，在记忆形成中发挥作用。众所周知，VGF衍生的多肽可以调节突触的可塑性、生殖行为和能量平衡。最近的人类遗传SNP图谱发现了一个VGF多态，该多态导致VGF在524位氨基酸后提前终止，消除了几个具有生物活性的VGF多肽和调节分泌所需的一个α-螺旋区域。这项建议中包含的初步数据显示，VGF C端肽具有抗抑郁效果，并调节海马神经元的电兴奋性和海马片中突触的可塑性，这与VGF基因敲除小鼠在空间记忆任务(如Morris水迷宫)和情景恐惧条件反射中的表现受损一致。在R21阶段的目标1中，我们将建立两个小鼠模型，将人VGF等位基因敲击到小鼠VGF基因座上，编码全长的人VGF(氨基酸1-615)或SNP截短的VGF(氨基酸1-524)。在R33阶段的目标1中，我们将在这些小鼠模型中测试人VGF的表达和功能，确定这种多态的携带者是否容易患抑郁症和认知障碍，就像那些BDNF表达和/或信号异常的人面临记忆和行为障碍的风险一样。VGF基因敲入小鼠的表现将在空间和背景恐惧记忆任务中，以及在抑郁和焦虑测试中进行测试。总体而言，拟议的实验将调查VGF、VGF衍生多肽和人类VGF基因的特定多态在调节海马区突触可塑性、抑郁和海马区依赖记忆中所起的作用。与公共健康相关：描述控制认知和行为的分子和机制将有助于加深对大脑功能和记忆的理解，这两者显然都会受到衰老、阿尔茨海默氏症或肌萎缩侧索硬化症等退行性疾病以及抑郁症等情绪障碍的影响。对公众健康：神经营养生长因子在神经系统中起着调节大脑发育和功能的关键作用，但很少有人发现由神经营养因子诱导并有助于记忆形成和行为的候选基因。表征控制认知和行为的分子和机制将有助于加深对大脑功能和记忆的理解，这两者显然都受到衰老、阿尔茨海默氏症或肌萎缩侧索硬化症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.