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

基本信息

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
项目类别：
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

项目摘要

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过程中神经元网络过度活跃的基础失调。异常的突触连接和表达小白蛋白（PV）的中间神经元的功能减退已被证实研究表明，它会导致多种神经发育障碍（例如自闭症谱系障碍）的抑制受损障碍（ASD）、精神分裂症（SCZ）和癫痫症。控制光伏突触接线的机制仍在研究中调查，因为已确定的数量相对较少。 Ephs 和 ephrins 是一类受体酪氨酸激酶（RTK）及其配体，已知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。 PV 中间神经元中 EphB 过度表达显示出对体周突触形成的负调节。该效应可能是由于接触依赖性 Eph/ephrin 信号传导介导的排斥，因为 EphB/ephrin-B 相互作用可以介导细胞排斥。星形胶质细胞表达肝配蛋白-B1（EphB 受体的配体），并可能影响抑制性突触的发育和通过与神经元 Eph 受体的相互作用来维持。事实上，我们实验室最近的工作表明星形细胞肝配蛋白-B1 负向调节兴奋性突触形成，但正向调节抑制性突触发育中小鼠而非成年小鼠 CA1 海马中兴奋性神经元 (Ex) 的形成和抑制。然而，星形细胞肝配蛋白-B1 控制体周抑制性突触发育的机制并且功能没有描述。初步数据显示 PV 阳性周围细胞的具体减少删除星形细胞肝配蛋白-B1 后的突触。该提案的重点是（1）确定perisomatic是否星形细胞肝配蛋白 B1 发育缺失后，由于 PV- 的具体变化，抑制作用发生改变诱发反应或其他周围靶向中间神经元，例如胆囊收缩素（CCK）中间神经元是否也受到影响；(2) 确定星形细胞肝配蛋白-B1 是否正向调节体周抑制性突触通过从 PV 纽扣上去除 EphB 受体来形成 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来确定体周抑制神经支配受星形胶质细胞 ephrin-B1 发育缺失和过度表达的影响，并研究潜在的机制。拟议的研究将描述星形胶质细胞介导的促进体周细胞的新机制抑制性突触形成，可用作治疗神经发育障碍的治疗靶点失调。