Analysis of Arp2/3 activity as a major driver of dendritic spinogenesis

Arp2/3 活性作为树突棘发生主要驱动因素的分析

基本信息

批准号：
9045178
负责人：
Erin Faith Spence
金额：
$ 3.53万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9045178
关键词：
AMPA Receptors Actins Address Adhesions Adult Alzheimer&apos s Disease Autistic Disorder Automobile Driving Biological Neural Networks Brain Brain Diseases Child Complex Data Dendritic Spines Dependovirus Development Disease Electrophysiology (science)Epilepsy Etiology Excitatory Synapse Exhibits Filopodia Future Genetic Glutamate Receptor Head Image Intellectual functioning disability Knockout Mice Knowledge Laboratories Lead Learning Link Maintenance Mediating Memory Mission Modification Molecular Morphology Mus N-Methylaspartate Neurobiology Neurodevelopmental Disorder Neurons Positioning Attribute Prevention Process Proteins Publishing Regulation Role Schizophrenia Side Signal Transduction Staging Structure Surface Synapses Techniques Testing Time United States National Institutes of Health Vertebral column Whole-Cell Recordings Work base complement C2a developmental disease experience gain of function in vivo in vivo imaging inhibitor/antagonist insight loss of function neurodevelopment novel polymerization postsynaptic programs public health relevance research study synaptogenesis tool

项目摘要

DESCRIPTION (provided by applicant) Excitatory spinogenesis (dendritic spine formation) is a key neurodevelopmental process that begins with filopodia formation, leads to axonal contact, spine maturation, recruitment of AMPA type glutamate receptors, and functional synapse formation. Later, in adulthood, actin-rich spine synapses undergo both rapid changes in morphology as well as slower alterations in spine turnover that are associated with experience and are thought to encode long-term modifications in neural network connectivity. However, the underlying mechanisms and regulation of these stages of spine regulation are poorly understood. This proposal will test the role of Arp2/3, a critical activator of actin polymerization, in these developmental milestones and experience driven processes. It will also determine how its activity may be fine-tuned during these processes. This will be accomplished by using two new lines of conditional knockout mice in combination with electrophysiology and in vivo imaging of spine development and plasticity. Overall, the anticipated results of this study will significantly enhance our understanding of dendritic filopodia initiation, maturation, and plasticity. As many child and adult onset brain disorders, including autism, intellectual disability, schizophrenia, Alzheimer's Disease, and epilepsy are associated with abnormal spine synapses, these results can be expected to lead to new insights into potential etiologies associated with these disorders.

描述（由申请人提供）兴奋性脊柱发生（树突棘形成）是一个关键的神经发育过程，从丝状伪足形成开始，导致轴突接触、脊柱成熟、AMPA 型谷氨酸受体的募集和功能性突触形成。随后，在成年期，富含肌动蛋白的脊柱突触经历这两种过程。形态的快速变化以及脊柱周转的缓慢变化与经验相关，并被认为编码神经网络连接的长期变化。然而，这些阶段的潜在机制和调节。该提案将测试 Arp2/3（肌动蛋白聚合的关键激活剂）在这些发育里程碑和经验驱动过程中的作用，并将确定其活性在这些过程中如何进行微调。总体而言，这项研究的预期结果将显着增强我们对树突状丝状伪足的起始、成熟和发育的理解。由于许多儿童和成人发病的脑部疾病，包括自闭症、智力障碍、精神分裂症、阿尔茨海默病和癫痫都与异常的脊柱突触有关，因此这些结果有望为与这些疾病相关的潜在病因学提供新的见解。