A role for ephrins-A2, -A3, & -A5 in excitatory synaptic development and function

肝配蛋白-A2、-A3 的作用，

• 批准号: 8686084
• 负责人: Rachel Wurzman
• 金额: $ 1.47万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8686084
• 关键词: AMPA Receptors; Acute; Address; Adult; Affect; Age; Aging; Animal Model; Autistic Disorder; Basal Ganglia; Behavior; Behavioral; Binding; CDK6-associated protein p18; Cell Separation; Cell physiology; Cell surface; Cells; Complex; Confocal Microscopy; Corpus striatum structure; Data; Dendrites; Dendritic Spines; Development; Disease; Dopamine D1 Receptor; Dopamine D2 Receptor; Electrophysiology (science); Eph Family Receptors; Ephrin-A2; Ephrins; Epigenetic Process; Etiology; Event; Excitatory Synapse; Exhibits; Face; Family; Functional disorder; Gene Deletion; Genetic; Genetic Polymorphism; Genetic Screening; Genotype; Gilles de la Tourette syndrome; Glutamate Receptor; Glutamates; Goals; Golgi Apparatus; Grooming; Image; Individual; Knowledge; Label; Learning; Life; Link; Measures; Mediating; Modeling; Molecular; Morphology; Motor; Motor Activity; Movement; Mus; Mutation; N-Methyl-D-Aspartate Receptors; Neurologic; Neurons; Patch-Clamp Techniques; Pathway interactions; Physiological; Physiology; Population; Preparation; Property; Proteins; Relative (related person); Research; Role; Sensory; Severities; Signaling Molecule; Site; Slice; Staining method; Stains; Synapses; Synaptic Transmission; Testing; Thinking; Time; Transgenic Mice; Transgenic Organisms; Vertebral column; age related; aged; axonal guidance; base; behavioral impairment; biocytin; density; developmental disease; genetic risk factor; interest; member; migration; neurodevelopment; neuropsychiatry; neurotransmission; postnatal; postsynaptic; promoter; receptor; research study; synaptic function; synaptogenesis; trafficking

DESCRIPTION (provided by applicant): Complex thoughts and movements require the integration of topographically organized cortical information about sensory, motor, and motivational states. These integrated networks involve corticostriatal synapses on dendritic spines of medium spiny projection neurons (MSNs), which are organized into unique compartments within the striatum. Epigenetic and genetic factors that alter the expression of molecules regulating the normal development of striatal neuronal compartments, corticostriatal afferent organization, or synaptic physiology could be involved in the etiology of the neuropsychiatric disorders associated with the striatum. Thus, my proposal aims are to identify a role for members of one molecular family of cell-surface signaling molecules, the A-class ephrins, in the proper development of striatal circuitry. Eph/ephrins are compelling candidate molecules that could participate in developmental events necessary to regulate the proper formation of striatal compartments and corticostriatal synaptogenesis due to their ability to regulate neuronal migration, axonal pathway topography and dendritic morphology, as well as modulate synaptic function via glutamate receptor trafficking. Mice with genetic deletions of ephrins-A2, -A3, and -A5 have disorganized striatal sub compartments and display differences in locomotor activity levels, repetitive facial grooming, and perseverance of inappropriate motor strategies during learning. These observations suggest that certain A- ephrins could differentially affect anatomical and physiological features essential for normal behaviors associated with corticostriatal function. It is currently unknown whether changes in the relative expression of ephrin-A2, -A3, and/or -A5 affect synaptic development or neurotransmission at corticostriatal synapses. Therefore, this research will include electrophysiology studies to examine changes in glutamate receptor trafficking and stereological studies of morphology to measure changes in dendrites of medium spiny neurons (MSNs), the main projection neurons in the striatum. Two subtypes of MSNs are distinguished by dopamine receptor D1 or D2 expression and these form the "direct" and "indirect" basal ganglia pathways, respectively. As many neuropsychiatric disorders linked to striatal dysfunction are thought to involve a functional imbalance between these two pathways, it is of particular interest to understand the effect that changes in the relative proportion of A-ephrins might have on excitatory physiology in these two populations of MSNs. This proposal entails use of unique transgenic mice expressing fluorescent marker proteins in each MSN subtype in combination with genetic deletions of ephrins-A2, -A3, and/or -A5. This model permits assessment of glutamate receptor activity and dendritic morphology in D1+ vs. D2+ MSNs. The guiding hypothesis is that changes in glutamatergic synaptic transmission and dendritic morphology will occur differentially in D1+ versus D2+ MSNs of mice with specific deletions of ephrins-A2/3/5. These studies will thus evaluate genetic factors that could contribute at multiple levels to the etiology of developmental neuropsychiatric disorders.

描述（由申请人提供）：复杂的思想和运动需要整合有关感官，运动和动机状态的地形组织的皮质信息。这些集成的网络涉及中等棘投射神经元（MSN）的树突状刺上的皮质纹状体突触，这些突触被组织成纹状体内的独特隔室。改变了调节纹状体神经元区室，皮质纹状体传入组织或突触生理学的正常发育的分子表达的表观遗传因素和遗传因素可能与与纹状体相关的神经精神疾病的病因涉及。因此，我的建议目的是确定一个细胞表面信号分子（A级ephrins）在纹状体回路的正常发展中的作用。 EPH/Ephrins是令人信服的候选分子，可以参与所必需的发展事件，以调节纹状体室和皮质骨膜突触发生，因为它们可以调节神经元迁移，轴突途径形象和树突形态和树突形态和通过胶凝受体调节型胶凝功能。 Ephrins -A2，-a3和-a5具有遗传缺失的小鼠纹状体子隔室混乱，并且在学习过程中表现出运动水平，重复的面部修饰以及不适当的运动策略的差异。这些观察结果表明，某些A-源自与皮质纹状体功能相关的正常行为必不可少的解剖学和生理特征差异化。目前尚不清楚ephrin -A2，-a3和/或-a5的相对表达是否会影响皮质纹状体突触的突触发育或神经传递。因此，这项研究将包括电生理学研究，以检查谷氨酸受体运输的变化和形态学的立体学研究，以测量纹状体中的主要投射神经元的中刺神经元（MSNS）的树突变化。 MSN的两个亚型由多巴胺受体D1或D2表达区分开，它们分别形成“直接”和“间接”基底神经节途径。由于许多与纹状体功能障碍相关的神经精神疾病都被认为涉及这两种途径之间的功能失衡，因此特别有趣的是，了解A-磷素相对比例的相对比例的变化可能对这两个MSN群体中的兴奋性生理的变化的影响。该建议需要使用独特的转基因小鼠，在每个MSN亚型中表达荧光标记蛋白，并将其与以Ephrins -A2，-a3和/或-a5的遗传缺失结合使用。该模型允许评估D1+与D2+ MSN中谷氨酸受体活性和树突形态。指导假设是，谷氨酸能突触传递和树突形态的变化将在D1+中与ephrins-a2/3/5的特定缺失的小鼠的D2+ MSN差异化。因此，这些研究将评估可能在多个层次上为发育神经精神疾病的病因做出多个层次的遗传因素。