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关于感觉、运动和动机状态的地形图组织的皮质信息。这些整合的网络涉及中棘投射神经元(MSN)树突棘上的皮质纹状体突触，这些MSN在纹状体内被组织成独特的隔室。表观遗传和遗传因素改变调节纹状体神经室、皮质纹状体传入组织或突触生理正常发育的分子的表达，可能参与纹状体相关神经精神障碍的病因学。因此，我的建议的目的是确定细胞表面信号分子的一个分子家族的成员，A类肾上腺素，在纹状体回路的正确发展中所起的作用。Eph/ephins是一类很有吸引力的候选分子，由于它们能够调节神经元的迁移、轴突通路的形态和树突的形态，以及通过谷氨酸受体运输来调节突触功能，因此可以参与调节纹状体脑室和皮质纹状体突触发生所必需的发育事件。携带-A2、-A3和-A5基因缺失的小鼠纹状体亚区紊乱，在运动活动水平、重复的面部梳理以及在学习过程中坚持不适当的运动策略方面表现出差异。这些观察表明，某些A-肾上腺素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和生理特征。目前尚不清楚ewitin-A2、-A3和/或-A5相对表达的变化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，以及体视学研究，以测量纹状体中的主要投射神经元中的中棘神经元树突的变化。根据多巴胺受体D1或D2的表达，MSN分为两种亚型，它们分别形成“直接”和“间接”的基底节通路。由于许多与纹状体功能障碍相关的神经精神障碍被认为涉及这两条通路之间的功能失衡，因此了解A-肾上腺素相对比例的变化可能对这两类MSN的兴奋生理学产生的影响是特别有意义的。这项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，并结合遗传缺失的eparins-A2、-A3和/或-A5。该模型可以评估D1+和D2+MSN的谷氨酸受体活性和树突形态。这些研究的指导假设是，在eaffins-A2/3/5特定缺失的小鼠的D1+和D2+MSN中，谷氨酸能突触传递和树突形态的变化将不同地发生。因此，这些研究将在多个水平上评估可能在发育性神经精神障碍的病因中起作用的遗传因素。