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： 抑制性电路受损被认为是神经发育中多动神经元网络的基础 疾病。表达中间神经元的白蛋白（PV）的异常突触接线和功能障碍已是 证明会导致几种神经发育障碍（例如自闭症谱系）的抑制作用受损 疾病（ASD），精神分裂症（SCZ）和癫痫。控制PV突触布线的机制仍在 调查，因为相对较少。以弗所和以弗林是一类受体酪氨酸激酶 （RTK）及其配体，这些配体涉及各种神经元发展过程 包括细胞迁移，轴突引导和突触发生。 PV中间神经元中的EPHB过表达已经 表现为负调节围次突触的形成。效果可能是由于接触依赖性 EPH/Ephrin信号传导介导的Ephb/Ephrin-B相互作用介导的排斥可以介导细胞排斥。 星形胶质细胞表达Ephrin-B1，EPHB受体的配体，可能会影响抑制性突触的发展和 通过与神经元素受体的相互作用进行维护。确实，我们实验室的最新工作表明 星形胶质细胞Ephrin-B1负调节兴奋性突触形成，但积极调节抑制性突触 在发育中的CA1海马中，但不是成年小鼠的兴奋性神经元（EX）的形成和抑制。 但是，星形胶质细胞Ephrin-B1控制围层抑制性突触的发育的机制 和功能尚未描述。初步数据表明，PV阳性周围的特定降低 删除星形胶质细胞Ephrin-B1后突触。该提议的重点是（1）确定是否存在perisaticatic 由于PV-的特异性变化，星形细胞Ephrin-B1发育缺失后，抑制作用改变了 诱发的反应或其他临界靶性中间神经元（例如胆囊动蛋白（CCK）中间神经元）是否是 还受到影响，并且（2）确定星形胶质细胞Ephrin-b1是否积极地调节par抑制性突触 通过从PV胸子中去除EPHB受体的形成，以防止EX和PV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，活细胞成像和生物化学，以确定临界抑制性神经 受到星形胶质细胞Ephrin-B1的发育缺失和过表达的影响，并研究了基础 机制。拟议的研究将描述新型星形胶质细胞介导的机制，促进了perisation。 抑制性突触形成，可以用作治疗神经发育的治疗靶点 疾病。