Imaging the origin of dendritic spine abnormalities in fragile X mice

脆弱 X 小鼠树突棘异常起源的成像

基本信息

批准号：
8079999
负责人：
Carlos Portera-Cailliau
金额：
$ 12.02万
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：
2010
资助国家：
美国
起止时间：
2010-07-10 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8079999
关键词：
4-methoxy-7-nitroindolinyl-glutamate Abbreviations Acids Actins Acute Address Affect Age Agonist Animal Disease Models Autistic Disorder Axon Brain Calcium Cells Computer software Cycloleucine Cytoskeleton Data Defect Dendrites Dendritic Spines Development Dicarboxylic Acids Dimethyl Sulfoxide Disease Ear Employee Strikes Esters Exhibits FMR1 FXTAS Family Figs - dietary Filopodia Fragile X Syndrome Future Genetic Glutamate Receptor Glutamates Green Fluorescent Proteins Growth Growth Cones Guanosine Triphosphate Phosphohydrolases Hippocampus (Brain)Image Individual Inherited Knockout Mice Knowledge Laboratories Length Link Long-Term Depression Long-Term Potentiation Mediating Mental Retardation Metabotropic Glutamate Receptors Microscopy Molecular Target Monitor Morphogenesis Mus Mutant Strains Mice N-Methylaspartate Neocortex Neonatal Nervous system structure Neurons Positioning Attribute Principal Investigator Process Property Proteins Receptor Signaling Recruitment Activity Research Personnel Role Signal Transduction Slice Structure Synapses Techniques Testing Testis Text Therapeutic Training Tremor/Ataxia Syndrome Vertebral column Work alpha-methyl-4-carboxyphenylglycine cell motility clinically relevant clinically significant density design gamma-Aminobutyric Acid hippocampal pyramidal neuron in vivo innovation metabotropic glutamate receptor type 1 mouse model neocortical novel postnatal programs pyridine research study response rho synaptogenesis two-photon

项目摘要

DESCRIPTION (provided by applicant): We want to investigate the mechanisms responsible for dendritic spine abnormalities in Fragile X syndrome (FXS). FXS is the most common inherited cause of autism and mental retardation. A clear link between the functional and structural (increased density and length of spines) abnormalities in FXS has not been established. A very similar defect in spines has been found in a knockout mouse model of FXS. Spines in FXS resemble dendritic filopodia, which are spine precursors. We show that in developing mouse neocortical neurons, filopodia are replaced by spines in the second postnatal week. Interestingly, the greatest differences in dendritic protrusions between wild type and fragile X mice occur at 1 week of age, and diminish thereafter. It is conceivable that anomalies of filopodia in the first postnatal days are even more striking in the knockout mice, but this has not been explored. Our preliminary data also reveal that dendritic protrusions are longer and more densely packed when neuronal activity is blocked, so it is possible that spontaneous activity is reduced in FXS. Fragile X mice exhibit excessive group I metabotropic glutamate receptor (mGluR)-mediated long-term depression. But a direct link between abnormal mGluR signaling and spine dysgenesis has not yet been discovered. Here, we show that filopodia elongate in response to glutamate and note that others have shown that spines elongate with stimulation of group I mGluRs. We want to test the general hypothesis that a defect in filopodia, linked to abnormal group I mGluR signaling and/or to decreased neuronal activity occurs in FXS, and might impair their ability to mature into spines. Innovative and cutting-edge microscopy techniques will be used. First, we will look for abnormalities of filopodia in pyramidal neurons of fragile X mice with in vivo two-photon imaging in the first postnatal days. Next, we will examine whether spontaneous neuronal activity is reduced in neonatal fragile X mice, using two-photon calcium imaging of hundreds of neurons simultaneously. Finally, we will use two-photon glutamate uncaging to study whether glutamate-mediated elongation of filopodia is disrupted in FXS and whether mGluRs participate in this phenomenon. The experiments in this proposal are designed to identify novel molecular targets for therapeutics in FXS. Because spine abnormalities are common to several other types of mental retardation and autism disorders, these studies are of broad clinical significance.

描述（由申请人提供）：我们想研究导致脆弱X综合征（FXS）树突状脊柱异常的机制。 FXS是自闭症和智力低下的最常见的继承原因。尚未建立FXS中功能和结构（刺的密度增加和长度）之间的明确联系。在FXS的基因敲除小鼠模型中发现了非常相似的缺陷。 FXS中的刺类似于脊柱前体的树突状丝状。我们表明，在开发小鼠新皮质神经元时，丝状霉菌在第二周后被棘所取代。有趣的是，野生型和脆弱的X小鼠之间的树突状突起的最大差异发生在1周龄，此后减少。可以想象，在产后的第一个时代，丝状虫的异常在淘汰小鼠中更加惊人，但这尚未得到探讨。我们的初步数据还表明，当神经元活性被阻断时，树突状突起更长，更密集，因此FXS中可能会降低自发活性。脆弱的X小鼠表现出过度的I组代谢型谷氨酸受体（MGLUR）介导的长期抑郁症。但是，尚未发现MGLUR信号传导和脊柱发病障碍之间的直接联系。在这里，我们表明丝霉素会响应谷氨酸，并注意到其他人已经表明，刺刺会随着I组mglurs的刺激而细长。我们想检验一般假设，即丝状菌缺陷与异常的MGlur信号传导和/或降低神经元活性有关，可能会在FXS中发生，并且可能会损害其成熟到脊椎的能力。将使用创新和尖端的显微镜技术。首先，我们将在脆弱的X小鼠的金字塔神经元中寻找丝状神经元的异常，并在产后的第一天具有体内两光子成像。接下来，我们将使用数百个神经元的两光钙成像同时研究新生儿脆弱X小鼠的自发神经元活性。最后，我们将使用两光子谷氨酸液体进行研究，以研究谷氨酸介导的丝状伸长率是否在FXS中破坏了丝氨酸的伸长率以及MGLURS是否参与了这种现象。该提案中的实验旨在确定FXS中治疗剂的新分子靶标。由于脊柱异常对于其他几种类型的智力低下和自闭症疾病是共同的，因此这些研究具有广泛的临床意义。