Imaging dendritic spine abnormalities and circuit defects in fragile X mice.

对脆弱 X 小鼠的树突棘异常和电路缺陷进行成像。

基本信息

批准号：
8839262
负责人：
Carlos Portera-Cailliau
金额：
$ 31.16万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8839262
关键词：
Address Affect Agonist Animal Model Area Autistic Disorder Axon Behavioral Brain Brain Stem Calcium Cells Chickens Child Childhood Clinical Cognition Cognitive Creativeness Defect Dendritic Spines Development Developmental Delay Disorders Disease Docking Electron Microscopy Electrophysiology (science)Emotions Excitatory Synapse Exhibits Experimental Designs FMRP Fragile X Mental Retardation Protein Fragile X Syndrome Functional disorder Genes Health Hypersensitivity Image Imaging Techniques Impairment Individual Inherited Knockout Mice Knowledge Lead Learning Memory Mental Retardation Microscopy Minor Mus Mutant Strains Mice Neurodevelopmental Disorder Neurons Pathway interactions Pharmaceutical Preparations Pharmacology Phenotype Population Psyche structure RNA Interference Research Role Seizures Sensory Sensory Deprivation Signal Pathway Staging Structural defect Structure Surveys Symptoms Synapses Synaptic plasticity Testing Translating Vertebral column Vesicle Vibrissae Wild Type Mouse barrel cortex base design egg environmental enrichment for laboratory animals experience hippocampal pyramidal neuron in vivo in vivo imaging neuropsychiatry neuroregulation noradrenergic patch clamp presynaptic research study response sensory stimulus synaptic function synaptogenesis theories two-photon

项目摘要

DESCRIPTION (provided by applicant): Fragile X syndrome (FXS) is the most common inherited form of intellectual impairment and the most common single gene cause of autism. Research in Fmr1 knockout (KO) mice, an animal model of FXS, has identified two major defects in the brain. The first is a structural abnormality in dendritic spines, the major recipiens of excitatory synapses in the cortex, and the second is a functional abnormality in synaptic and experience- dependent plasticity. Using in vivo two-photon microscopy, we and others have identified a developmental delay in the stabilization and maturation of dendritic spines of cortica pyramidal neurons in Fmr1 KO mice, which may be one of the earliest synaptic defects in FXS. Now, we will test the hypothesis that circuit remodeling triggered by sensory experience is intimately tied to the spine dynamics and size, thereby reconciling the structural and functional phenotypes of Fmr1 KO mice. We will also investigate synapse integrity at the ultrastructural level with electron microscopy, as well as the dynamics of axons and their boutons during cortical development, in order to ascertain whether they are also altered in mutant mice. In addition, using in vivo two-photon calcium imaging and electrophysiology to record neuronal activity in intact circuits, we have shown that pyramidal neurons in Fmr1 KO mice show abnormally high firing rates and synchrony, which could explain the deficits in learning and low seizure threshold in these mice. Here, we will test the hypothesis that this network hyperexcitability translates into problems with sensory-evoked activity and we will investigate whether these circuit-level problems in KO mice can be rescued with drugs that affect brainstem neuromodulation and inhibitory pathways. The experimental design employs cutting edge in vivo imaging techniques and seeks to address important knowledge gaps and controversial issues in FXS. Because dendritic spine abnormalities and many of the signaling pathways regulated by the fragile X mental retardation protein are also implicated in other neurodevelopmental disorders, we believe that our unique synapse-to- circuit approach has a very high significance and is likely to be of broad importance to many types of autism and mental impairment.

描述（由申请人提供）：脆弱的X综合征（FXS）是最常见的智力障碍形式，也是自闭症的最常见单基因原因。 FMR1敲除（KO）小鼠的研究是FXS的动物模型，已经确定了大脑中的两个主要缺陷。第一个是树突状棘的结构异常，皮质中的主要兴奋性突触量，第二个是突触和经验依赖性可塑性的功能异常。使用体内两光子显微镜，我们和其他人已经确定了FMR1 KO小鼠中Cortica锥体神经元的树突状稳定和成熟的发育延迟，这可能是FXS中最早的突触缺陷之一。现在，我们将测试以下假设：感官体验触发的电路重塑与脊柱动力学和大小密切相关，从而对FMR1 KO小鼠的结构和功能表型进行了调解。我们还将通过电子显微镜在超微结构水平的超微结构水平上进行突触完整性，以及在皮质发育过程中轴突及其胸子的动力学，以确定突变小鼠中是否也改变了它们。此外，使用体内两光子钙成像和电生理学记录完整电路中的神经元活性，我们已经表明，FMR1 KO小鼠中的金字塔神经元异常高的触发速率和同步性，这可以解释这些小鼠中学习和低癫痫发作阈值的缺陷。在这里，我们将检验以下假设：该网络过度兴奋能够转化为感官诱发活动的问题，我们将研究是否可以用影响脑干神经调节和抑制途径的药物来挽救KO小鼠中的这些电路级问题。实验设计采用了体内成像技术的前沿，并试图解决FXS中重要的知识差距和有争议的问题。由于树突状脊柱异常和许多由脆弱的X智力低下蛋白调节的信号传导途径也与其他神经发育障碍有关，因此我们认为我们独特的突触到电路方法具有很高的意义，并且对许多自动抗动物和心理障碍可能具有广泛的重要性。