Long-lasting effects of anesthetics on synapse development and plasticity

描述（由申请人提供）：本项目的目标是阐明全身麻醉剂对突触发育和功能的长期影响，并开发治疗策略以预防早期暴露于麻醉剂引起的突触和学习缺陷。麻醉剂通常用于婴儿和幼儿的外科手术。最近的研究表明，在广泛的突触形成期间，重复和长时间的麻醉剂暴露可能导致以后生活中的学习和行为障碍。然而，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，我们将研究在大脑发育的特定阶段，单次和重复暴露于麻醉剂对突触可塑性和功能的影响。通过使用体内双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对学习依赖性突触可塑性和以后的生活功能产生长期的有害影响。此外，我们将检验以下假设，即氯胺酮或七氟烷等麻醉剂的不良反应是由于持续的多巴胺能神经传递功能减退，而多巴胺能神经传递活性的药理学增强是由于 α-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）受体可减轻这种作用。拟议中的实验将使我们能够获得重要的机械见解如何早期暴露于麻醉导致学习和行为障碍。他们还将帮助建立新的治疗策略，旨在挽救麻醉对发育中大脑的有害影响。

DESCRIPTION (provided by applicant): 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 α-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.