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: 10096510
• 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/10096510
• 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; Structure; 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.

项目总结