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Mechanisms Underlying Activity-Dependent Interneuron Development

活动依赖性中间神经元发育的潜在机制

基本信息

批准号：
8721600
负责人：
Natalia Vanesa De Marco Garcia
金额：
$ 1.8万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-23 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8721600
关键词：
Ablation Action Potentials Advisory Committees Affect Applications Grants Area Award Axon Brain Cajal-Retzius cells Calcium Candidate Disease Gene Cells Characteristics Communities Cues Defect Dendrites Development Development Plans Disease Educational process of instructing Educational workshop Electrophysiology (science)Electroporation Environment Epilepsy Etiology Excision GABA Receptor Gene Targeting Genetic Genetic Programming Glutamate Receptor Glutamates Goals Grant Human Pathology Image Individual Institutes Interneurons Laboratories Link Maps Marketing Mediating Methods Molecular Biology Morphology Mus N-Methyl-D-Aspartate Receptors Nature Neurobiology Neurologic Neurons Neurosciences Neurotransmitters Occupations Output Pathogenesis Pathology Pathway interactions Pattern Phase Physiological Play Population Positioning Attribute Postdoctoral Fellow Process Pyramidal Cells Radial Readiness Research Resolution Role Schizophrenia Science Shapes Signal Pathway Signal Transduction Sodium Somatosensory Cortex Source Staging Synapses Techniques Time Training Vasoactive Intestinal Peptide Viral Work Writing abstracting autism spectrum disorder calretinin career development cohort design developmental genetics gamma-Aminobutyric Acid improved in utero in vivo inhibitory neuron interdisciplinary collaboration medical schools migration nervous system development neuron component neuronal excitability neuropsychiatry postnatal programs receptor relating to nervous system research study skills transmission process virus genetics

项目摘要

DESCRIPTION (provided by applicant): This application is for the K99/R00 Pathway to Independence award. I am currently a senior postdoctoral fellow in the Fishell lab at the NYU-School of Medicine and I have an extensive background in molecular biology and mouse genetics. My career development plan is designed to acquire theoretical and practical training in electrophysiology under the guidance of Drs. Gord Fishell and Bernardo Rudy. In addition, the development plan is aimed at strengthening my presentation, grant-writing and teaching skills. A postdoctoral advisory committee (PAC) will oversee my progress and assess my readiness to enter the job market and make the transition to an independent laboratory. Finally, I will take courses and workshops to develop a background in neurological and neuropsychiatric disease entities with the goal of improving my ability to consider my research findings in the context of potential links to human pathologies. The K99 portion of the award would take place within the Smilow Neuroscience Program at NYU-School of Medicine. This program, in combination with the larger Neuroscience community at NYU (Center for Neural Science and Skirball Institute), will provide a superb academic environment in which to complete my training and successfully transition to an independent academic position. Scientific Abstract: Recent experimental evidence has revealed that intrinsic genetic programs endow GABAergic interneurons with an early subtype identity. It is also known that interneurons participate in correlated network activiy during development. Indeed, my previous work indicates that the radial migration and morphological development of calretinin and reelin but not vasoactive intestinal peptide interneurons, the major subtypes derived from the caudal ganglionic eminence (CGE), are activity-dependent. Furthermore we have found that glutamatergic drive is essential for mediating the activity required for the proper development of axons and dendrites towards the end of the first postnatal week. However, the mechanisms by which activity regulates interneuron maturation are not fully understood. This proposal is aimed at revealing the identity of the neuronal types that provide interneurons with the neurotransmitters necessary for laminar targeting, and for the proper formation of axons and dendrites (Aim 1). In addition, this project will explore the role of glutamate receptors in morphological development (Aim 2). Finally, a long-term aim of this research plan is to describe the connectivity pattern of developing interneurons as they integrate into cortical circuits, and to assess how neuronal activity may regulate the process by which this pattern is generated (Aim 3). A variety of neuronal cohorts populate the cortex during the first postnatal week, when activity-dependent maturation of interneuron subtypes takes place. Glutamatergic cell cohorts present during this time include Cajal-Retzius cells, glutamatergic transient cells, subplate cells and pyramidal cells. Due to thei spatial and temporal distribution, these cohorts are well suited to provide interneurons with the glutamatergic drive that is fundamental for their morphological development. Glutamate release from each individual cohort will be genetically blocked to assess the impact of these populations on interneuron maturation (Subaim 1a). GABAergic transmission is also prominent at early stages of cortical development and may contribute to laminar targeting. To assess the role of GABA in radial migration, GABA receptors will be blocked pharmacologically (Subaim 1b). While our previous experiments have indicated a requirement for glutamate in morphological development, the mechanism responsible for activity-sensitive maturation is not understood. Due to the developmental role of NMDA receptors, our experiments will focus on the study of these ionotropic receptors during interneuron development. The cell-autonomous consequences of NMDA receptor removal in CGE interneuron will be assessed. Our analysis will also include the study of the signaling pathways operating downstream of these receptors (Aim 2). After interneurons undergo migration and develop characteristic morphologies, they integrate into cortical circuits. However, the identity of synaptic inputs to specific subsets of CGE interneurons are unknown. Monosynaptic viral tracing techniques will be used in combination with in utero electroporation to reveal the pattern of connectivity of maturing interneurons (Subaim 3a). In addition, our experiments will assess the impact of perturbing neuronal activity on the integration of interneurons into nascent cortical circuits (Subaim 3b). The experiments in this grant proposal will be carried out in vivo in the mouse somatosensory cortex. The principles that will emerge from these studies, however, are expected to apply to other regions of the cortex as well. A better understanding of interneuron development and GABAergic circuit formation over a potentially broad set of cortical areas is likely to contribute to our understanding of the pathogenesis of diseases in which interneuron defects are thought to play a role. In addition, the experimental approach presented in this proposal exemplifies the advantage of interdisciplinary collaboration within the field of neurobiology. Indeed, it is my conviction that the integration of both the conceptual approach and experimental techniques from two particular subfields, developmental genetics and electrophysiology, will continue to advance our understanding of CNS function and pathology.

描述（由申请人提供）：此申请是K99/R00独立之路奖。我目前是纽约大学医学院费希尔实验室的高级博士后，我在分子生物学和小鼠遗传学方面有广泛的背景。我的职业发展计划是在博士的指导下获得电生理学的理论和实践训练。戈德·费舍尔和贝尔纳多·鲁迪。此外，发展计划的目的是加强我的演讲，拨款写作和教学技能。一个博士后咨询委员会（PAC）将监督我的进展，评估我是否准备好进入就业市场，并过渡到一个独立的实验室。最后，我将参加课程和研讨会，以发展神经和神经精神疾病实体的背景，目的是提高我在与人类病理潜在联系的背景下考虑我的研究成果的能力。该奖项的K99部分将在纽约大学医学院的Smilow神经科学项目中进行。这个项目，结合纽约大学更大的神经科学社区（神经科学中心和Skirball研究所），将提供一个极好的学术环境，让我完成训练，并成功过渡到一个独立的学术职位。科学摘要：最近的实验证据表明，内在遗传程序赋予gaba能中间神经元早期亚型身份。在发育过程中，中间神经元也参与了相关的网络活动。事实上，我之前的工作表明，calretinin和reelin的径向迁移和形态发育，而不是血管活性肠肽中间神经元，来源于尾神经节隆起（CGE）的主要亚型，是活动依赖的。此外，我们发现谷氨酸驱动对于调节轴突和树突在出生后第一周结束时的正常发育所需的活动是必不可少的。然而，活动调节中间神经元成熟的机制尚不完全清楚。这一建议旨在揭示为中间神经元提供层流靶向所必需的神经递质以及轴突和树突的正确形成所必需的神经元类型的身份（Aim 1）。此外，本项目将探讨谷氨酸受体在形态发育中的作用（Aim 2）。最后，本研究计划的一个长期目标是描述发育中的中间神经元整合到皮层回路时的连接模式，并评估神经元活动如何调节这种模式产生的过程（目的3）。各种各样的神经元群在出生后的第一周内填充皮层，此时中间神经元亚型的活动依赖成熟发生。在此期间存在的谷氨酸能细胞群包括Cajal-Retzius细胞、谷氨酸能瞬时细胞、亚板细胞和锥体细胞。由于它们的空间和时间分布，这些队列非常适合为中间神经元提供谷氨酸能驱动，这是它们形态发育的基础。每个个体队列的谷氨酸释放将被遗传阻断，以评估这些群体对中间神经元成熟的影响（Subaim 1a）。gaba能传递在皮层发育的早期阶段也很突出，可能有助于层流靶向。为了评估GABA在径向迁移中的作用，将通过药物阻断GABA受体（Subaim 1b）。虽然我们之前的实验表明在形态发育中需要谷氨酸，但负责活动敏感成熟的机制尚不清楚。由于NMDA受体的发育作用，我们的实验将重点研究这些嗜离子受体在中间神经元发育过程中的作用。将评估CGE中间神经元中NMDA受体去除的细胞自主后果。我们的分析还将包括对这些受体下游信号通路的研究（目的2）。中间神经元经过迁移并形成特征形态后，整合到皮层回路中。然而，CGE中间神经元的特定亚群的突触输入的身份