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: 8654369
• 负责人: Sunghee Cho
• 金额: $ 39.25万
• 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/8654369
• 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.

描述（由申请人提供）：由于中风诱导结构可塑性和行为适应，促进中风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）在中枢神经系统修复和可塑性中发挥着关键作用。 bdnf 基因前结构域的单核苷酸多态性 (SNP) 在人类中出现频率较高。然而，这种SNP对中枢神经系统恢复的影响一直存在争议。目前的提案通过使用在两个等位基因 (BDNFMet/Met) 或一个等位基因 (BDNF+/Met) 中含有人源化 SNP 的小鼠调查 BDNF SNP 对中风后运动恢复的影响程度来解决这一争议。尽管在急性期损伤更大，但与野生型相比，BDNFMet/Met 小鼠在中风恢复阶段表现出意想不到的运动/步态功能增加，特别是同侧后肢，并且未受伤半球的纹状体体积增加（WT）小鼠。伴随着该半球兴奋性突触标记基因表达的增加。由于活性调节的 BDNF 分泌对于抑制性突触的成熟很重要，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 等位基因通过减少导致突触兴奋的抑制性突触来促进代偿性运动恢复，并且对侧纹状体肥大。目标 1 将检验 BDNFMet 等位基因通过对侧纹状体的影响促进运动恢复的假设。使用遭受缺血性中风的 WT、BDNF+/Met 和 BDNFMet/Met 小鼠，我们将评估运动功能，分析分区体积，并通过评估对侧纹状体急性药物灭活后的行为变化来解决对侧纹状体的重要性。目标 2 将检验 BDNFMet 等位基因诱导突触变化并将纹状体突触平衡转变为兴奋状态的假设。将研究详细的神经元形态和突触特性的变化。我们发现BDNFMet/Met小鼠的炎症受体CD36（在先天免疫和伤口愈合中发挥作用）及其配体血小板反应蛋白（TSP）的表达增加，后者参与兴奋性突触的形成。因此，我们将测试目标 3 中 CD36 通路通过对侧纹状体中的突触兴奋促进 BDNFMet 等位基因诱导的突触可塑性和运动恢复的假设。CD36、TSP、兴奋性和抑制性突触标记将在 WT 和 BDNFMet/Met 中进行评估中风后的小鼠。 CD36 在 BDNFMet 等位基因诱导的脑可塑性中的重要性将在缺乏 CD36 的 BDNFMet/Met 小鼠或已用 CD36 拮抗剂治疗的小鼠中得到解决。从研究中获得的见解将提供一种方法来预测与 BDNF SNP 携带者相关的中风恢复过程。此外，确定激活 CD36 通路的关键窗口可能会产生促进不携带 SNP 的中风患者运动恢复的治疗策略。