Elucidating the Role of Astrocytic Ephrin-B1 in Inhibitory Circuit Development in the CA1 Hippocampus

阐明星形细胞 Ephrin-B1 在 CA1 海马抑制回路发育中的作用

• 批准号: 10680409
• 负责人: Samantha Sutley
• 金额: $ 4.02万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10680409
• 关键词: Adhesions; Adhesives; Affect; Astrocytes; Biochemistry; Cells; Cholecystokinin; Cues; Data; Development; Developmental Process; Electrophysiology (science); Endocytosis; Eph Family Receptors; Ephrin B Receptor; Ephrin-B1; Ephrins; Epilepsy; ErbB4 gene; Excision; Excitatory Synapse; Functional disorder; Genes; Goals; Hippocampus; Human; Hyperactivity; Immunohistochemistry; Impairment; In Vitro; Inhibitory Synapse; Interneurons; Investigation; Knock-out; Lead; Ligands; Maintenance; Mediating; Mus; Neuregulin 1; Neurodevelopmental Disorder; Neurons; Parvalbumins; Pathology; Phosphorylation; Publishing; Pyramidal Cells; Receptor Protein-Tyrosine Kinases; Reporting; Research; Role; Schizophrenia; Signal Transduction; Simian virus 40; Synapses; Testing; Time; Viral Vector; Western Blotting; Work; autism spectrum disorder; axon guidance; cell motility; excitatory neuron; gephyrin; hippocampal pyramidal neuron; in vivo; interdisciplinary approach; live cell imaging; mouse model; nerve supply; new therapeutic target; novel; optogenetics; overexpression; patch clamp; postnatal; prevent; receptor; receptor expression; response; synaptic inhibition; synaptogenesis; therapeutic target; uptake

Project Summary/Abstract: Impaired inhibitory circuits are thought to underlie hyperactive neuronal networks in neurodevelopmental disorders. Aberrant synaptic wiring and hypofunction of parvalbumin (PV) expressing interneurons has been shown to contribute to impaired inhibition in several neurodevelopmental disorders such as autism spectrum disorder (ASD), schizophrenia (SCZ) and epilepsy. Mechanisms that control PV synaptic wiring are still under investigation, as relatively few have been identified. Ephs and ephrins are a class of receptor tyrosine kinases (RTK) and their ligands, which are known to be involved in a diverse array of neuronal developmental processes including cell migration, axon guidance, and synaptogenesis. EphB overexpression in PV interneurons has been shown to negatively regulate perisomatic synapse formation. The effect was possibly due to contact-dependent repulsion mediated by Eph/ephrin signaling as EphB/ephrin-B interactions can mediate cellular repulsion. Astrocytes express ephrin-B1, the ligand for EphB receptor, and may affect inhibitory synapse development and maintenance through its interactions with neuronal Eph receptors. Indeed, recent work in our lab has shown that astrocytic ephrin-B1 negatively regulates excitatory synapse formation but positively regulates inhibitory synapse formation and inhibition of excitatory neurons (Ex) in the CA1 hippocampus of developing, but not adult mice. However, the mechanism by which astrocytic ephrin-B1 controls perisomatic inhibitory synapse development and function has not been described. Preliminary data show a specific reduction in PV-positive perisomatic synapses following deletion of astrocytic ephrin-B1. The focus of this proposal is to (1) determine if perisomatic inhibition is altered following developmental deletion of astrocytic ephrin-B1 due to changes specifically in PV- evoked responses or if other perisomatic targeting interneurons, such as cholecystokinin (CCK) interneurons are also affected and (2) to determine if astrocytic ephrin-B1 positively regulates perisomatic inhibitory synapse formation through removal of EphB receptors from PV boutons, preventing repulsion between Ex and PV cells. I propose to use multidisciplinary approaches, including immunohistochemistry, whole cell electrophysiology, optogenetics, live cell imaging, and biochemistry to determine the perisomatic inhibitory innervation that is affected by developmental deletion and overexpression of astrocytic ephrin-B1, and to investigate the underlying mechanism. The proposed research will describe novel astrocyte mediated mechanisms promoting perisomatic inhibitory synapse formation, which could be utilized as a therapeutic target for treating neurodevelopmental disorders.

项目概要/摘要： 抑制回路受损被认为是神经发育过程中过度活跃的神经元网络的基础。 紊乱异常的突触连接和表达小白蛋白（PV）的中间神经元功能低下已经被证实是一种神经元损伤。 在一些神经发育障碍如自闭症谱系中， 自闭症（ASD）、精神分裂症（SCZ）和癫痫。控制PV突触连接的机制仍处于 调查，因为相对较少被发现。Ephs和ephrin是一类受体酪氨酸激酶 (RTK)以及它们的配体，已知它们参与多种神经元发育过程 包括细胞迁移、轴突引导和突触发生。EphB在PV中间神经元中的过表达已经被证实是一种新的免疫抑制剂。 显示负调节体周突触形成。这种效应可能是由于接触依赖性 由于EphB/肝配蛋白-B相互作用可以介导细胞排斥，因此Eph/肝配蛋白信号传导介导的排斥可以通过Eph/肝配蛋白信号传导介导。 星形胶质细胞表达EphB受体的配体ephrin-B1，并可能影响抑制性突触发育， 通过与神经元Eph受体的相互作用维持。事实上，我们实验室最近的工作表明， 星形胶质细胞ephrin-B1负调节兴奋性突触形成但正调节抑制性突触 在发育中但不是成年小鼠的CA 1海马中兴奋性神经元（Ex）的形成和抑制。 然而，星形胶质细胞ephrin-B1控制体周抑制性突触发育的机制 并且功能没有被描述。初步数据显示，PV阳性的外周组织中 星形胶质细胞ephrin-B1缺失后的突触。本建议的重点是（1）确定是否perisomatic 抑制作用在星形胶质细胞ephrin-B1的发育缺失后改变，这是由于PV-1的特异性变化。 诱发的反应，或者如果其他体周靶向中间神经元，如胆囊收缩素（CCK）中间神经元， 也受到影响和（2）确定是否星形胶质细胞ephrin-B1积极调节体周抑制性突触 通过从PV结上去除EphB受体，防止Ex和PV细胞之间的排斥形成EphB。 我建议使用多学科方法，包括免疫组织化学、全细胞电生理学， 光遗传学、活细胞成像和生物化学来确定躯体周围抑制性神经支配， 星形胶质细胞ephrin-B1的发育缺失和过度表达的影响，并探讨其潜在的 机制拟议的研究将描述新的星形胶质细胞介导的机制， 抑制性突触形成，其可用作治疗神经发育的治疗靶点 紊乱