Serotonergic modulation of excitatory synapse formation and maturation during development

发育过程中兴奋性突触形成和成熟的血清素调节

基本信息

批准号：
10513816
负责人：
Won Chan Oh
金额：
$ 38.37万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2025-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10513816
关键词：
Age Agreement Animal Model Antidepressive Agents Behavior Behavioral Blood Brain Brain Diseases Calcium Calcium Signaling Cerebral cortex Chronic Color Communication Data Dendrites Dendritic Spines Development Disease Electrophysiology (science)Environmental Risk Factor Excitatory Synapse Exposure to Fluoxetine Functional disorder Genetic Glutamates Goals Growth Human Image Impairment Incidence Individual Interneurons Invaded Investigation Knowledge Life Literature Localized Lesion Measures Mediating Molecular Mus Neurodevelopmental Disorder Neuronal Dysfunction Neurons Neurotransmitters Outcome Pathogenesis Pathology Pharmaceutical Preparations Physiological Prefrontal Cortex Pregnancy Pregnant Women Presynaptic Terminals Receptor Activation Receptor Signaling Research Resolution Risk Role Selective Serotonin Reuptake Inhibitor Serotonergic System Serotonin Signal Transduction Site Somatostatin Stimulus Symptoms Synapses Testing Time Vertebral column Work autism spectrum disorder autistic cell type cognitive process density experience experimental study fetal fluorescence lifetime imaging gamma-Aminobutyric Acid hippocampal pyramidal neuron improved infancy insight neonatal exposure neural circuit neuronal excitability novel novel therapeutic intervention offspring optogenetics pharmacologic postnatal postsynaptic prenatal exposure psychologic receptor response social social deficits spatiotemporal synaptic function synaptogenesis tool two-photon

项目摘要

Project Summary Autism Spectrum Disorders (ASDs) comprise a group of severe neurodevelopmental disorders that are typified by communication deficits and social impairment. Given that the onset of symptoms occurs by the age of 3, it is largely agreed that neuronal dysfunction arises during early brain development. A developing brain shows a remarkable capacity for plastic changes in response to experiences; thus, its development is most vulnerable to the environmental factors that can derail normal brain function. In utero exposure to drugs that raise blood 5HT levels, including selective serotonin reuptake inhibitors (SSRIs), has demonstrated behavioral and psychological deficits in offspring that closely resemble autistic symptoms in both animals models and human studies. In order to understand how these alterations arise, it is necessary to first understand the basic mechanisms of serotonergic modulation of brain function. Formation and stabilization of excitatory synapses are known to be essential for the initial establishment of functional neural circuits. Conversely, disrupted synapse development impairs neuron function and is thought to underlie the pathology of multiple neurodevelopmental disorders. PFC is densely innervated by serotonergic axon terminals and associated with higher cognitive processes that may be disrupted in illnesses such as ASDs. Despite a wealth of literature examining the role of 5HT in modulating behavior and in the pathogenesis of brain disorders, little is known at the cellular and molecular level about the role of 5HT in early cortical development, and particularly the postsynaptic 5HT mechanisms that modulate synapse development in the developing PFC. In the present study, we utilize a novel combination of tools including two-color, two-photon uncaging that enables precise release of 5HT and glutamate neurotransmitters, calcium imaging, electrophysiology, and optogenetic stimulation of genetically-targeted 5HT neurons to test our central hypothesis that 5HT signaling promotes the initiation of excitatory synapse formation and controls the maturation of excitatory synapses during brain development. Guided by strong preliminary data, we will examine this hypothesis in two specific aims: 1) Determine the role of 5HT signaling in lowering the threshold for induction of activity-dependent synapse formation. 2) Define the actions of 5HT on activity-dependent, input-specific and heterosynaptic spine stabilization. Results from these studies will further our understanding of the unique and detailed mechanisms by which 5HT regulates brain development, with critical relevance to cellular underpinnings of neurodevelopmental disorders. In the U.S., approximately 13% of pregnant women use SSRIs, which typically increase fetal 5HT levels. We expect that our results will highlight new avenues into the investigation of the pathophysiology underlying neurodevelopmental disorders resulting from early perturbation of 5HT signaling.

项目概要自闭症谱系障碍 (ASD) 包括一组严重的神经发育障碍，其典型特征是由于沟通缺陷和社交障碍。鉴于症状出现在 3 岁时，人们普遍认为神经元功能障碍是在大脑早期发育过程中出现的。发育中的大脑显示出根据经验做出可塑性变化的卓越能力；因此，其发展最容易受到可能破坏正常大脑功能的环境因素。在子宫内接触升高血液 5HT 的药物水平，包括选择性血清素再摄取抑制剂（SSRIs），已证明行为和心理在动物模型和人类研究中，后代的缺陷与自闭症症状非常相似。为了要了解这些变化是如何发生的，有必要首先了解这些变化的基本机制大脑功能的血清素调节。已知兴奋性突触的形成和稳定对于功能神经回路的初步建立至关重要。相反，突触发育受到干扰损害神经元功能，被认为是多种神经发育障碍病理学的基础。全氟碳化物受到血清素能轴突末端的密集支配，并与可能的更高认知过程相关因自闭症谱系障碍（ASD）等疾病而受到干扰。尽管有大量文献研究 5HT 在调节中的作用在细胞和分子水平上，人们对大脑疾病的行为和发病机制知之甚少。 5HT 在早期皮质发育中的作用，特别是调节突触后 5HT 机制发育中的 PFC 中的突触发育。在本研究中，我们利用了一种新颖的工具组合包括双色、双光子解禁，能够精确释放 5HT 和谷氨酸神经递质，对基因靶向 5HT 神经元进行钙成像、电生理学和光遗传学刺激，以测试我们的中心假设是 5HT 信号传导促进兴奋性突触形成的启动并控制大脑发育过程中兴奋性突触的成熟。在强有力的初步数据的指导下，我们将研究该假设有两个具体目的：1) 确定 5HT 信号传导在降低诱导阈值中的作用活动依赖性突触形成。 2) 定义 5HT 对活动依赖、输入特定和异突触脊柱稳定。这些研究的结果将进一步加深我们对独特且 5HT 调节大脑发育的详细机制，与细胞基础密切相关神经发育障碍。在美国，大约 13% 的孕妇使用 SSRIs，通常增加胎儿 5HT 水平。我们预计我们的结果将突出调查该问题的新途径 5HT 信号传导早期扰动导致神经发育障碍的病理生理学。