Cerebellum and cerebellar-regulated circuit contribution to Fragile X Syndrome

小脑和小脑调节回路对脆性 X 综合征的影响

• 批准号: 10403964
• 负责人: Peter T. Tsai
• 金额: $ 56.92万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10403964
• 关键词: Acute; Applications Grants; Automobile Driving; Behavior; Behavior Disorders; Behavioral; Blinking; Cell physiology; Cerebellar Diseases; Cerebellum; Child; Data; Decision Making; Development; Disease; Electrophysiology (science); Evaluation; FMR1; Fragile X Syndrome; Functional disorder; Genetic; Genetic Models; Healthcare; Hypersensitivity; Image; Impairment; Individual; Injections; Knock-out; Lifestyle-related condition; Light; Link; Lobule; Mediating; Modeling; Molecular; Morphology; Mutant Strains Mice; Nervous System Physiology; Neurocognitive; Neurodevelopmental Disorder; Parietal; Pathogenesis; Pathology; Pathway interactions; Phenotype; Physiology; Play; Prevalence; Purkinje Cells; Regulation; Role; Sensory; Slice; Subcellular Anatomy; Synaptic plasticity; Therapeutic; Tremor/Ataxia Syndrome; Viral; association cortex; autism spectrum disorder; base; care burden; disability; improved; in vivo; molecular targeted therapies; mouse model; mutant; mutant mouse model; neuroregulation; pre-clinical; relating to nervous system; restoration; social; social deficits; targeted treatment; therapy development

Project Summary No targeted therapies exist for treatment of Autism Spectrum Disorders (ASD), as the underlying mechanisms remain poorly understood. Recent studies implicate the cerebellum in the pathogenesis of ASD, and we have recently shown that cerebellar dysfunction is sufficient to generate ASD-relevant behaviors. However, the contribution of cerebellar dysfunction to these behaviors in Fragile X Syndrome (FXS) is unknown. FXS is the most significant monogenic cause of ASD, and cerebellar dysfunction has been implicated in the pathogenesis of both ASD and FXS. Previous studies have demonstrated important roles for Fmr1 in the cerebellum – from dendritic morphology to synaptic plasticity; however, the contribution of cerebellar dysfunction to autism-relevant behaviors in FXS remains unknown. In this proposal, we hypothesize and present preliminary data to support that cerebellar Fmr1 dysfunction is sufficient to generate ASD behaviors, including social dysfunction and sensory hypersensitivity. To evaluate this hypothesis, we propose in Aim1 to establish the role for Purkinje cell Fmr1 in the regulation of ASD-relevant behaviors and to further evaluate electrophysiological and molecular mechanisms that are disrupted upon loss of cerebellar Fmr1. With evidence that cerebellar dysfunction contributes to ASD behaviors, we also hypothesized and have generated preliminary data to support specific cerebellar lobule CrusI involvement in ASD-related behaviors and circuit connections between this lobule and the parietal association cortex, a region implicated in ASD and in sensory processing. In Aim2, we will delineate the involvement of right CrusI – parietal association cortex circuits in ASD-relevant behaviors and investigate the impact of circuit modulation on ASD-relevant behaviors and cortical hyper-excitability in the cerebellar FXS mouse model. Lastly, we also hypothesize and show preliminary data to support that normalization of cerebellar function might itself be sufficient to ameliorate ASD-related behaviors in a global (whole body knockout) model of FXS. In Aim3, we will delineate the benefit of reintroduction of Fmr1 specifically into the cerebellum in an otherwise global Fmr1 mutant mouse. In addition, we will further evaluate the potential benefit of cerebellar neuromodulation in this global Fmr1 mutant mouse model on behavior and cortical hyper-excitability. Taken together, in this proposal, we will establish the roles for Fmr1 in the cerebellum and establish its contribution to autism-related behaviors. We will additionally examine the molecular mechanisms driving these contributions and examine the benefits of reintroduction of Fmr1 within the cerebellum in an otherwise global Fmr1 mutant. Lastly, we will examine the benefit of cerebellar neuromodulation on ASD-relevant behaviors in cerebellar and global FXS mouse models. Thus, these studies will not only further our understanding of basic molecular and circuit mechanisms of ASD-relevant behaviors in FXS but will also shed light on potential circuit and molecular targets for therapy for FXS.

项目概要 自闭症谱系障碍 (ASD) 的潜在机制尚不存在靶向疗法 仍然知之甚少。最近的研究表明小脑与 ASD 的发病机制有关，我们已经 最近表明，小脑功能障碍足以产生 ASD 相关行为。然而， 小脑功能障碍对脆性 X 综合征 (FXS) 的这些行为的影响尚不清楚。 FXS 是自闭症谱系障碍 (ASD) 最重要的单基因病因，小脑功能障碍与该病有关 ASD 和 FXS 的发病机制。先前的研究已经证明 Fmr1 在 小脑——从树突形态到突触可塑性；然而，小脑的贡献 FXS 中自闭症相关行为的功能障碍仍然未知。在这个提案中，我们假设并 提供初步数据支持小脑 Fmr1 功能障碍足以产生 ASD 行为， 包括社交功能障碍和感觉过敏。为了评估这个假设，我们在 Aim1 中提出 确定浦肯野细胞 Fmr1 在 ASD 相关行为调节中的作用并进一步评估 小脑 Fmr1 缺失后会被破坏的电生理学和分子机制。 有证据表明小脑功能障碍会导致自闭症谱系障碍 (ASD) 行为，我们还做出了假设并进行了研究 生成初步数据以支持特定小脑小叶 CrusI 参与 ASD 相关行为 以及该小叶和顶叶联合皮层（与自闭症谱系障碍有关的区域）之间的电路连接 在感觉处理中。在 Aim2 中，我们将描绘右 CrusI（顶叶联合皮质）的参与 电路在 ASD 相关行为中的作用，并研究电路调制对 ASD 相关行为的影响 以及小脑 FXS 小鼠模型中的皮质过度兴奋性。 最后，我们还假设并显示初步数据来支持小脑功能正常化 在 FXS 的全局（全身敲除）模型中，它本身可能足以改善 ASD 相关行为。 在 Aim3 中，我们将以另一种方式描述将 Fmr1 重新引入小脑的好处 全球Fmr1突变小鼠。此外，我们将进一步评估小脑的潜在益处 该全球 Fmr1 突变小鼠模型中的神经调节对行为和皮质过度兴奋性的影响。 综上所述，在本提案中，我们将确定 Fmr1 在小脑中的角色，并建立其 对自闭症相关行为的贡献。我们还将进一步研究驱动这些的分子机制 贡献并检查在小脑内重新引入 Fmr1 的好处 Fmr1 突变体。最后，我们将研究小脑神经调节对 ASD 相关行为的益处 小脑和全局 FXS 小鼠模型。因此，这些研究不仅将加深我们对基础知识的理解。 FXS 中 ASD 相关行为的分子和电路机制，但也将揭示潜在的电路 以及 FXS 治疗的分子靶点。