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：
7391375
负责人：
Carlos Portera-Cailliau
金额：
$ 8.65万
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 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7391375
关键词：
4-methoxy-7-nitroindolinyl-glutamate ACPD Abbreviations Acids Actins Acute Address Affect Age Agonist Animal Disease Models Autistic Disorder Axon Brain Calcium Cells Chromosome Pairing 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 Ganciclovir Genetic Glutamate Receptor Glutamates Green Fluorescent Proteins Growth Growth Cones Guanosine Triphosphate Phosphohydrolases Hippocampus (Brain)Image Individual Inherited Knock-out 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 Rate Receptor Signaling Recruitment Activity Research Personnel Role Signal Transduction Slice Structure Synapses Techniques Testing Testis Text Therapeutic Training Tremor/Ataxia Syndrome Vertebral column Week Work alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid alpha-methyl-4-carboxyphenylglycine amino 3 hydroxy 5 methylisoxazole 4 propionate cell motility clinically relevant clinically significant day density design dihydroxyphenylethylene glycol 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

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 anomaliesof 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.

我们想要研究导致脆性 X 综合征树突棘异常的机制（FXS）。 FXS 是自闭症和智力低下最常见的遗传原因。之间有明确的联系 FXS 的功能和结构（脊柱密度和长度增加）异常尚未得到证实已确立的。在 FXS 基因敲除小鼠模型中也发现了非常相似的脊柱缺陷。刺在 FXS 类似于树突状丝状伪足，它们是脊柱前体。我们表明，在小鼠新皮质的发育过程中神经元、丝状伪足在出生后第二周被棘取代。有趣的是，最伟大的野生型和脆性 X 小鼠之间的树突突起差异出现在 1 周龄时，并且此后减少。可以想象，产后最初几天的丝状伪足异常现象更为严重。在基因敲除小鼠中发挥作用，但这尚未得到探索。我们的初步数据还表明，树突状当神经元活动受阻时，突起会变得更长、更密集，因此有可能 FXS 中的自发活动减少。脆性 X 小鼠表现出过量的 I 类代谢型谷氨酸受体（mGluR）介导的长期抑郁症。但异常的 mGluR 信号传导与尚未发现脊柱发育不全。在这里，我们表明丝状伪足响应于延长谷氨酸盐，并注意到其他人已经表明刺会随着 I 组 mGluR 的刺激而伸长。我们想要检验丝状伪足缺陷与异常 I 组 mGluR 信号传导相关的一般假设和/或 FXS 中神经元活动减少，并可能损害它们成熟为脊柱的能力。将使用创新和尖端的显微镜技术。首先，我们要寻找异常情况出生后第一天体内双光子成像显示脆性 X 小鼠锥体神经元的丝状伪足。接下来，我们将使用以下方法检查新生脆性 X 小鼠的自发神经元活动是否减少同时对数百个神经元进行双光子钙成像。最后，我们将使用双光子谷氨酸解笼锁以研究谷氨酸介导的丝状伪足伸长是否在 FXS 和 mGluR 是否参与了这一现象。本提案中的实验旨在确定 FXS 治疗的新分子靶点。因为脊柱异常对于其他几种疾病来说很常见类型的精神发育迟滞和自闭症障碍，这些研究具有广泛的临床意义。