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: 10535356
• 负责人: Samantha Sutley
• 金额: $ 3.9万
• 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/10535356
• 关键词: Adhesions; Adhesives; Affect; Astrocytes; Biochemistry; Cells; Cholecystokinin; 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 (Brain); Human; Hyperactivity; Immunohistochemistry; Impairment; In Vitro; Inhibitory Synapse; Interneurons; Investigation; Knock-out; Lead; Ligands; Maintenance; Mediating; Mus; Neuregulin 1; Neurodevelopmental Disorder; Neurons; Parvalbumins; Pathology; 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; 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.

项目摘要/摘要： 抑制回路受损被认为是神经发育中过度活跃的神经元网络的基础 精神错乱。表达小白蛋白(PV)的中间神经元突触连接异常和功能低下 研究表明，在一些神经发育障碍中，如自闭症谱系，抑制功能受损 精神障碍(ASD)、精神分裂症(SCZ)和癫痫。控制PV突触连接的机制仍在研究中 调查，因为确定的相对较少。Ephs和Ephins是一类受体酪氨酸激酶 (RTK)及其配体，已知参与一系列不同的神经元发育过程 包括细胞迁移、轴突引导和突触发生。EphB在PV中间神经元中的过度表达 显示负向调节骨周突触的形成。这种影响可能是由于接触依赖所致。 通过EphB/Ephin-B相互作用介导的EphB/Ephin信号介导的排斥力可以介导细胞排斥。 星形胶质细胞表达EphB受体的配体ePhin-B1，并可能影响抑制性突触的发育和 通过与神经元Eph受体的相互作用维持。事实上，我们实验室最近的研究表明 星形胶质细胞中的肾上腺素-B1负向调节兴奋性突触的形成，但正向调节抑制性突触 发育中而非成年小鼠CA1海马区兴奋性神经元(Ex)的形成和抑制 然而，星形细胞的ephin-B1控制智周抑制性突触发育的机制 和功能还没有被描述。初步数据显示，PV阳性的智齿周围症患者明显减少 星形细胞蛋白-B1缺失后的突触。这项建议的重点是(1)确定周围区是否 在发育过程中，星形细胞的ePhin-B1的缺失会改变抑制作用，这是由于PV- 诱发反应或其他周围靶向中间神经元，如CCK中间神经元是否 也受到影响，以及(2)确定星形细胞ePhin-B1是否正向调节智周抑制性突触 通过从光伏细胞上移除EphB受体而形成，防止Ex和光伏细胞之间的排斥。 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、活细胞成像和生化来确定周围抑制性神经支配，即 影响星形胶质细胞ephin-B1的发育缺失和过度表达，并探讨其潜在的 机制。这项拟议的研究将描述新的星形胶质细胞介导的促进周围肌的机制。 抑制突触形成，可作为治疗神经发育的靶点 精神错乱。