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

• 批准号: 10307105
• 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
• 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/10307105
• 关键词: Age; Animal Model; Antidepressive Agents; Behavior; Behavioral; Blood; Brain; Brain Diseases; Calcium; 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; Lesion; Life; Literature; Measures; Mediating; Molecular; Mus; Neurodevelopmental Disorder; Neuronal Dysfunction; Neurons; Neurotransmitters; Outcome; Pathogenesis; Pathology; Pharmaceutical Preparations; Pharmacology; Physiological; Prefrontal Cortex; Pregnancy; Pregnant Women; Presynaptic Terminals; Receptor Activation; 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; postnatal; postsynaptic; prenatal exposure; psychologic; receptor; response; social; social deficits; spatiotemporal; synaptic function; synaptogenesis; tool; two-photon

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.

项目摘要 自闭症谱系障碍（ASDS）包括一组严重的神经发育障碍 通过沟通不足和社会障碍。鉴于症状发作到3岁时发生，这是 在很大程度上同意，在早期大脑发育过程中会出现神经元功能障碍。一个发育的大脑显示 塑料变化的显着能力响应经验；因此，它的发展最容易受到影响 可能使正常脑功能脱轨的环境因素。在子宫内暴露于升血5HT的药物 包括选择性5-羟色胺再摄取抑制剂（SSRI）在内的水平已表现出行为和心理 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 要了解这些改变是如何出现的，有必要首先了解 脑功能的血清素能调节。已知兴奋性突触的形成和稳定是 最初建立功能性神经回路至关重要。相反，突触的破坏 损害神经元的功能，被认为是多种神经发育障碍的病理。 PFC 通过血清素能轴突末端密集地支配，并与较高的认知过程相关 在ASD等疾病中受到破坏。尽管大量文献研究了5HT在调节中的作用 行为和脑部疾病的发病机理，在细胞和分子水平上几乎不知道 5HT在早期皮质发育中的作用，尤其是调节后突触后的5HT机制 发育中的PFC突触发展。在本研究中，我们利用了新的工具组合 包括两种颜色的两光子脉冲，可以精确释放5HT和谷氨酸神经递质， 钙成像，电生理学和遗传靶向5HT神经元的光遗传学刺激测试我们 中心假设，即5HT信号传导促进了兴奋性突触形成的启动，并控制了 大脑发育过程中兴奋性突触的成熟。在强大的初步数据的指导下，我们将检查 这两个特定目的的假设：1）确定5HT信号在降低诱导阈值中的作用 活动依赖性突触形成。 2）定义5HT对活动依赖性，输入特异性和 异突触脊柱稳定。这些研究的结果将进一步了解我们对独特和 5HT调节大脑发育的详细机制，与细胞基础有关 神经发育障碍。在美国，大约13％的孕妇使用SSRI，通常 增加胎儿5HT水平。我们希望我们的结果将重点介绍新的途径 病理生理的基础神经发育障碍是由于5HT信号的早期扰动而导致的。