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: 8401070
• 负责人: Rachel Wurzman
• 金额: $ 2.98万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8401070
• 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. PUBLIC HEALTH RELEVANCE: Complex thoughts and movements require the integration of cortical information about sensory, motor, and motivational states at excitatory synapses on striatal medium spiny neurons (MSNs). Several neuropsychiatric disorders that are characterized by abnormal repetitive thoughts or behaviors have been linked to a functional imbalance in the relative activity of projections from MSNs expressing either D1 or D2 dopamine receptors. These studies will investigate how genetic deletions in specific members of the A-ephrin class of signaling molecules contribute to anatomical and functional abnormalities at corticostriatal synapses on D1+ versus D2+ MSNs, to increase understanding of the molecular factors that influence the development of these circuits as well as their role in the etiology of 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觉、运动和动机状态的地形组织的皮层信息。这些集成网络涉及中型多刺投射神经元（MSN）树突棘上的皮质纹状体突触，这些突触被组织成纹状体内独特的区室。改变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正常发育的分子表达的表观遗传和遗传因素可能参与与纹状体相关的神经精神疾病的病因学。因此，我的建议旨在确定细胞表面信号分子分子家族成员（A 类肝配蛋白）在纹状体电路正常发育中的作用。 Eph/ephrins 是引人注目的候选分子，可以参与调节纹状体区室的正确形成和皮质纹状体突触发生所必需的发育事件，因为它们能够调节神经元迁移、轴突通路拓扑结构和树突形态，以及通过谷氨酸受体运输调节突触功能。肝配蛋白-A2、-A3和-A5基因缺失的小鼠纹状体亚区混乱，并且在运动活动水平、重复性面部修饰以及学习过程中坚持不适当的运动策略方面表现出差异。这些观察结果表明，某些A-肝配蛋白可以不同地影响与皮质纹状体功能相关的正常行为所必需的解剖学和生理学特征。目前尚不清楚肝配蛋白-A2、-A3和/或-A5的相对表达的变化是否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，以及形态学的体视学研究，以测量中型多棘神经元（MSN）树突的变化，中型棘神经元是纹状体中的主要投射神经元。 MSN 的两种亚型通过多巴胺受体 D1 或 D2 表达来区分，它们分别形成“直接”和“间接”基底神经节通路。由于许多与纹状体功能障碍相关的神经精神疾病被认为涉及这两条通路之间的功能失衡，因此了解 A-ephrins 相对比例的变化可能对这两个 MSN 群体的兴奋性生理学的影响特别有意义。该提议需要使用在每种 MSN 亚型中表达荧光标记蛋白的独特转基因小鼠，并结合肝配蛋白-A2、-A3 和/或 -A5 的基因删除。该模型允许评估 D1+ 与 D2+ MSN 中的谷氨酸受体活性和树突形态。指导性假设是，在肝配蛋白-A2/3/5 特异性缺失的小鼠的 D1+ 和 D2+ MSN 中，谷氨酸突触传递和树突形态的变化将发生差异。因此，这些研究将评估可能在多个层面上影响发育性神经精神疾病病因的遗传因素。 公共健康相关性：复杂的思想和运动需要整合有关纹状体中棘神经元 (MSN) 兴奋性突触的感觉、运动和动机状态的皮层信息。一些以异常重复思想或行为为特征的神经精神疾病与表达 D1 或 D2 多巴胺受体的 MSN 投射相对活动的功能失衡有关。这些研究将调查 A-肝配蛋白类信号分子特定成员的基因缺失如何导致 D1+ 与 D2+ MSN 上皮质纹状体突触的解剖和功能异常，以增进对影响这些回路发育的分子因素及其在神经精神疾病病因学中的作用的了解。