Impact of BDNF SNP on stroke-induced plasticity and motor function

BDNF SNP 对中风引起的可塑性和运动功能的影响

• 批准号: 8450489
• 负责人: Sunghee Cho
• 金额: $ 39.32万
• 依托单位: WINIFRED MASTERSON BURKE MED RES INST
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8450489
• 关键词: Acute; Address; Affect; Alleles; American; Animal Model; Attention; Behavioral; Brain; Brain-Derived Neurotrophic Factor; CD36 gene; Codon Nucleotides; Contralateral; Corpus striatum structure; Dose; Equilibrium; Excitatory Synapse; Financial compensation; Frequencies; Gait; Gene Expression; Genes; Genetic; Hippocampus (Brain); Human; Hypertrophy; Impairment; Individual; Inflammation; Inflammatory; Inhibitory Synapse; Injury; Ipsilateral; Ischemic Stroke; Lead; Ligands; Limb structure; Link; Mediating; Methionine; Molecular; Morphology; Motor; Movement; Mus; Mutation; Natural Immunity; Nervous system structure; Neurons; Outcome; Pathway interactions; Patients; Phase; Phenocopy; Play; Population; Property; Recovery; Recovery of Function; Role; Side; Single Nucleotide Polymorphism; Stroke; Structure; Synapses; Synaptic plasticity; System; Testing; Therapeutic; Therapeutic Intervention; Thrombospondins; Valine; Vertebral column; Wild Type Mouse; Wound Healing; base; behavior change; behavior test; density; disability; experience; gait examination; improved; insight; middle cerebral artery; motor deficit; motor learning; neurotrophic factor; novel; prospective; receptor; relating to nervous system; repaired; scavenger receptor; stroke recovery

DESCRIPTION (provided by applicant): As stroke induces structural plasticity and behavioral adaptation, strategies that promote functional recovery following stroke have gained prospective attention. Brain-derived neurotrophic factor (BDNF) plays a critical role in CNS repair and plasticity. A single nucleotide polymorphism (SNP) of the prodomain of the bdnf gene occurs with high frequency in humans. However, the effect of this SNP on CNS recovery has been controversial. The current proposal addresses this controversy by investigating the extent to which BDNF SNP impacts motor recovery following stroke using mice that contain humanized SNP in both alleles (BDNFMet/Met) or one allele (BDNF+/Met). In spite of greater impairments during the acute phase, BDNFMet/Met mice displayed an unexpected increase in motor/gait function during the stroke recovery phase, especially in the ipsilateral hind limb, and increased striatal volume in the non-injured hemisphere compared to wild type (WT) mice. This was accompanied by increased gene expression of excitatory synaptic markers in this hemisphere. Since activity-regulated BDNF secretion is important for the maturation of inhibitory synapses, and this type of secretion is reduced in BDNFMet/Met neurons, we hypothesize that the BDNFMet allele promotes compensatory motor recovery by reducing the inhibitory synapses leading to synaptic excitation in, and hypertrophy of, the contralateral striatum. Aim 1 will test the hypothesis that the BDNFMet allele promotes motor recovery via effects in the contralateral striatum. Using WT, BDNF+/Met, and BDNFMet/Met mice subjected to ischemic stroke, we will assess motor functions, analyze sub-region volume, and address the importance of the contralateral striatum by assessing behavior changes after acute pharmacological inactivation of the contralateral striatum. Aim 2 will test the hypothesis that the BDNFMet allele induces synaptic changes and shifts synaptic balance to an excitatory status in the striatum. Detailed neuronal morphology and changes in synaptic properties will be investigated. We have shown that BDNFMet/Met mice display increased expression of the inflammatory receptor CD36, which functions in innate immunity and wound healing, and also of its ligand thrombospondins (TSPs) that are involved in the formation of excitatory synapses. We will therefore test the hypothesis that the CD36 pathway contributes to BDNFMet allele-induced synaptic plasticity and motor recovery through synaptic excitation in the contralateral striatum in Aim 3. CD36, TSPs, excitatory and inhibitory synaptic markers will be assessed in WT and BDNFMet/Met mice following stroke. The importance of CD36 in BDNFMet allele-induced brain plasticity will be addressed in BDNFMet/Met mice that lack CD36 or in mice that have been treated with a CD36 antagonist. The insight gained from the studies will provide a means to predict the course of stroke recovery relevant to BDNF SNP carriers. In addition, defining a critical window for activating the CD36 pathway may lead to therapeutic strategies for promoting motor recovery in stroke patients who do not carry the SNP. PUBLIC HEALTH RELEVANCE: Stroke is the leading cause of long-term disability in the American population. This study will investigate whether a mutation in the brain-derived neurotrophic factor (BDNF) gene affects long-term motor recovery following ischemic stroke and whether the effect occurs through an inflammatory receptor, CD36. Understanding the brain mechanisms involved in improving functional recovery will help to predict the course of recovery in stroke patients with the BDNF mutation and lead to potential therapeutic interventions.

描述（由申请人提供）：由于卒中诱导结构可塑性和行为适应，促进卒中后功能恢复的策略已获得前瞻性关注。脑源性神经营养因子（BDNF）在中枢神经系统的修复和可塑性中起着关键作用。bdnf基因前结构域的单核苷酸多态性（SNP）在人类中发生频率很高。然而，这种SNP对CNS恢复的影响一直存在争议。目前的提议通过使用在两个等位基因（BDNF Met/Met）或一个等位基因（BDNF+/Met）中含有人源化SNP的小鼠来研究BDNF SNP影响中风后运动恢复的程度来解决这一争议。尽管在急性期有更大的损伤，但与野生型（WT）小鼠相比，BDNFMet/Met小鼠在中风恢复期显示出运动/步态功能的意外增加，特别是在同侧后肢中，并且在未损伤的半球中显示出纹状体体积的增加。这是伴随着兴奋性突触标记在这个半球的基因表达增加。由于活性调节的BDNF分泌对于抑制性突触的成熟是重要的，并且这种类型的分泌在BDNFMet/Met神经元中减少，因此我们假设BDNFMet等位基因通过减少抑制性突触来促进代偿性运动恢复，从而导致对侧纹状体中的突触兴奋和肥大。目的1将检验BDNFMet等位基因通过对侧纹状体的作用促进运动恢复的假设。使用WT、BDNF+/Met和BDNF Met/Met缺血性卒中小鼠，我们将评估运动功能，分析亚区域体积，并通过评估对侧纹状体急性药物灭活后的行为变化来说明对侧纹状体的重要性。目的2将测试的假设，BDNFMet等位基因诱导突触的变化和转移突触平衡的兴奋状态在纹状体。详细的神经元形态和突触特性的变化将进行研究。我们已经表明，BDNFMet/Met小鼠表现出炎症受体CD 36的表达增加，其在先天免疫和伤口愈合中起作用，并且还表现出其配体血小板反应蛋白（TSP）的表达增加，其参与兴奋性突触的形成。因此，我们将测试的假设，CD 36通路有助于BDNFMet等位基因诱导的突触可塑性和运动恢复通过突触兴奋在对侧纹状体的目的3。中风后，将在WT和BDNFMet/Met小鼠中评估⑶ 36、TSP、兴奋性和抑制性突触标志物。将在缺乏CD 36的BDNFMet/Met小鼠或已用CD 36拮抗剂处理的小鼠中解决CD 36在BDNFMet等位基因诱导的脑可塑性中的重要性。从研究中获得的见解将提供一种预测与脑源性神经营养因子SNP携带者相关的中风恢复过程的方法。此外，定义激活CD 36通路的关键窗口可能会导致促进不携带SNP的中风患者运动恢复的治疗策略。 公共卫生相关性：中风是美国人口长期残疾的主要原因。这项研究将调查脑源性神经营养因子（BDNF）基因突变是否会影响缺血性中风后的长期运动恢复，以及这种影响是否通过炎症受体CD 36发生。了解参与改善功能恢复的大脑机制将有助于预测BDNF突变的中风患者的恢复过程，并导致潜在的治疗干预。