Transcriptional Mechanism underlying Neuronal Hyperexcitability in FXS

FXS 神经元过度兴奋的转录机制

• 批准号: 10746620
• 负责人: Nien-Pei Tsai
• 金额: $ 43.62万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10746620
• 关键词: Acute; Address; Affect; Anxiety; Apoptosis; Behavioral; Cancer Biology; Cell Cycle; Clinical Trials; Complex; Data; Defect; Developmental Delay Disorders; Disease model; Dissociation; Double Minutes; Down-Regulation; Epilepsy; Exhibits; FMR1; Female; Fragile X Syndrome; Future; Gene Expression; Genes; Genetic Transcription; Hippocampus; Hypersensitivity; In Vitro; Inherited; Intellectual functioning disability; Intention; Knock-out; Knockout Mice; Knowledge; Measures; Molecular; Mus; Neocortex; Neuronal Differentiation; Neurons; Patients; Phenotype; Predisposition; Prosencephalon; Publishing; Receptor Activation; Regulation; Reporting; Research; Research Priority; Role; Seizures; Sensory; Signal Transduction; Slice; Strategic Planning; Synapses; TP53 gene; Testing; Therapeutic; United States National Institutes of Health; Up-Regulation; Work; associated symptom; audiogenic seizure; autism spectrum disorder; design; effective therapy; excitatory neuron; improved; in vivo; inhibitor; male; metabotropic glutamate receptor type 1; mouse model; multi-electrode arrays; neocortical; neuronal excitability; novel; novel therapeutics; patch clamp; pharmacologic; response; social anxiety; transcription factor; transcriptome sequencing; ubiquitin-protein ligase

PROJECT SUMMARY/ABSTRACT Fragile X syndrome (FXS) patients show multiple symptoms associated with neuronal, synaptic, and circuit hyperexcitability, such as sensory hypersensitivity, anxiety, and seizures. Although multiple mechanisms have been proposed to explain hyperexcitability in FXS, an effective treatment remains unavailable, indicating the need for search for more specific therapeutic strategy. It is well accepted that exaggerated activity of Group 1 metabotropic glutamate receptors (Gp1 mGluRs) contributes in part to the hyperexcitability in FXS. Activation of Gp1 mGluRs has been shown to lead to robust elevation of intrinsic excitability of hippocampal excitatory neurons and seizure susceptibility in mice. Despite these observations, the molecular regulation and mechanisms underlying elevated neuronal excitability following activation of Gp1 mGluRs have been complex and remain unclear. To improve our understanding of Gp1 mGluR-associated neuronal hyperexcitability in FXS, our preliminary observations led us to study the tumor suppressor p53. Our recent studies discovered that the activity of tumor suppressor p53 is positively correlated with neuronal excitability in vitro and seizure susceptibility in vivo. Because our data showed that activation of Gp1 mGluR leads to activation of p53, and the transcription activity of p53 is basally elevated in the FXS mouse model, the Fmr1 KO mice, we hypothesize that activation of Gp1 mGluR promotes neuronal intrinsic excitability in part through p53-dependent gene transcription, and inhibition of p53 can ameliorate neuronal excitability defects in FXS. To test this hypothesis, we propose in Aim 1 to study the mechanism by which p53 contributes to Gp1 mGluR activation-induced elevation of neuronal excitability. We will follow by pharmacologically or genetically inhibiting p53 in Aim 2 to determine whether the hyperexcitability phenotypes in Fmr1 KO mice can be ameliorated. We expect our research as proposed will provide a new aspect to our understanding of FXS. In addition, with the deep knowledge of p53 in the field of cancer biology and our preliminary data identifying neuron-enriched target genes of p53, the proposed research has the potential to introduce many new concepts into the design of future treatment for FXS.

项目总结/摘要 脆性X综合征（FXS）患者表现出与神经元、突触和回路相关的多种症状。 过度兴奋，如感觉过敏、焦虑和癫痫发作。虽然有多种机制 虽然有人提出解释FXS的过度兴奋，但仍然没有有效的治疗方法，这表明 需要寻找更具体的治疗策略。人们普遍认为，第1组的夸大活动 代谢型谷氨酸受体（Gp1 mGluRs）部分地促成FXS中的超兴奋性。激活 已经显示Gp1 mGluRs导致海马兴奋性神经元的固有兴奋性的强烈升高， 神经元和癫痫易感性。尽管有这些观察结果，分子调控和 Gp1 mGluRs激活后神经元兴奋性升高的机制是复杂的 仍然不清楚。为了提高我们对FXS中Gp1 mGluR相关神经元过度兴奋的理解， 我们的初步观察引导我们研究肿瘤抑制因子p53。我们最近的研究发现， 肿瘤抑制因子p53活性与神经元兴奋性和癫痫易感性呈正相关 in vivo.因为我们的数据表明Gp1 mGluR的激活导致p53的激活，并且转录水平降低。 在FXS小鼠模型，Fmr1 KO小鼠中，p53的活性基本升高，我们假设， Gp1 mGluR部分通过p53依赖性基因转录促进神经元内在兴奋性， 抑制p53可以改善FXS中神经元兴奋性缺陷。为了验证这一假设，我们在Aim中提出 1研究p53参与Gp1 mGluR激活诱导的神经元凋亡的机制。 兴奋性我们将在目标2中通过抑制或遗传抑制p53来确定是否 可以改善Fmr1 KO小鼠中的过度兴奋表型。我们希望我们提出的研究将 为我们理解FXS提供了新的视角。此外，随着对p53在细胞凋亡领域的深入了解， 癌症生物学和我们的初步数据确定神经元富集的p53靶基因，拟议的研究 有可能将许多新概念引入FXS未来治疗的设计中。