Long-lasting effects of anesthetics on synapse development and plasticity

项目总结/摘要 这个项目的目标是阐明全身麻醉药对突触的长期影响 发展和功能，并制定治疗策略，以防止突触和学习缺陷 是由于过早暴露在麻醉剂下造成的麻醉剂通常用于婴儿的外科手术， 年幼的孩子。最近的研究表明，重复和长期的麻醉暴露，在这段时间内， 广泛的突触发生，可能导致以后生活中的学习和行为障碍。但 麻醉剂引起神经回路和学习障碍的长期缺陷的机制 仍然未知。在本申请中，我们将研究单次和重复暴露于 麻醉剂对大脑发育特定阶段的突触可塑性和功能的影响。通过使用体内两个- 光子显微镜结合新产生的谷氨酸和钙传感器，我们将确定 在出生后早期发育过程中反复暴露于麻醉剂是否具有长期的有害作用， 对学习依赖性突触可塑性和以后生活中的功能的影响。此外，我们将测试 假设氯胺酮或七氟烷等麻醉剂的不良反应是由于持续性 多巴胺能神经传递功能减退和药理学上增强多巴胺能神经递质活性 氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体或N-甲基-D-天冬氨酸（NMDA） 受体可以减轻这种影响。拟议的实验将使我们能够获得重要的机理 深入了解早期暴露于麻醉剂如何导致学习和行为障碍。他们还将帮助 建立新的治疗策略，旨在挽救麻醉对患者的不利影响， 大脑发育

PROJECT SUMMARY / ABSTRACT The goal of this project is to elucidate the long-term consequences of general anesthetics on synapse development and function, and to develop therapeutic strategies to prevent synaptic and learning deficits caused by early exposure to anesthesia. Anesthetics are commonly used for surgical operations in infants and young children. Recent studies suggest that repeated and prolonged anesthetic exposure, during the period of extensive synaptogenesis, can lead to learning and behavioral impairments later in life. However, the mechanisms by which anesthetics cause long-lasting deficits in neural circuits and learning impairments remain unknown. In this application, we will investigate the effects of single and repeated exposure to anesthetics on synaptic plasticity and function at specific stages of brain development. By using in vivo two- photon microscopy in combination with newly-generated glutamate and calcium sensors, we will determine whether repeated exposure to anesthetics during early postnatal development has long-lasting detrimental impacts on learning-dependent synaptic plasticity and function later in life. In addition, we will test the hypothesis that the adverse effects of anesthetics such as ketamine or sevoflurane are due to persistent hypofunction of glutamatergic neurotransmission and that pharmacological enhancement of the activities of ¿- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors or N-methyl-D-aspartate (NMDA) receptors would alleviate such effects. The proposed experiments will allow us to gain important mechanistic insights into how early exposure to anesthesia causes learning and behavioral impairments. They will also help establish novel treatment strategies directed at rescuing the detrimental effects of anesthesia on the developing brain.