Targeting PDZ to unravel early anesthetic exposure-produced cognitive dysfunction

靶向 PDZ 来解决早期麻醉暴露引起的认知功能障碍

基本信息

批准号：
9016565
负责人：
Roger A Johns
金额：
$ 38.21万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9016565
关键词：
Address Anesthetics Animals Behavioral Binding Binding Sites Biological Brain Breathing Cell Proliferation Cells Chemicals Clinical Cognitive Cohort Studies Data Dendritic Spines Development Exposure to Functional disorder Glutamates Goals Health Hippocampus (Brain)Image Impaired cognition Impairment In Vitro Investigation Isoflurane Learning Learning Disabilities Life Light Long-Term Potentiation Maintenance Mediating Memory Molecular Morphology Mutant Strains Mice Mutation N-Methyl-D-Aspartate Receptors Neonatal Neuraxis Neurocognitive Neurons Nitric Oxide Pathogenesis Play Postsynaptic Membrane Probability Protein Family Proteins Rattus Regulation Resistance Risk Factors Role Scaffolding Protein Site Slice Synapses Synaptic plasticity Time Vertebral column Vesicle clinically relevant inhibitor/antagonist mutant neonatal exposure nerve stem cell neural circuit neurogenesis neurotoxicity optogenetics overexpression postnatal postsynaptic presynaptic presynaptic density protein 95 prevent protein protein interaction social synaptic function synaptogenesis

项目摘要

DESCRIPTION (provided by applicant): Previous clinical cohort studies and animal studies have shown that early exposure to anesthetics is a significant risk factor for later development of learning disabilities. However, the underlying molecular mechanism is unclear. Several lines of evidence have indicated that impaired hippocampal neurogenesis and synaptogenesis may be involved in the mechanisms by which early anesthetic exposure produces long-term cognitive impairment, and that synaptic scaffolding protein PSD-95 PDZ domain-mediated protein-protein interactions and synaptic activities are involved in the regulation of neurogenesis and synaptogenesis in the hippocampus. Our previous studies have demonstrated that PDZ domain-mediated protein interactions are disrupted by clinically relevant concentrations of inhaled anesthetics. Recently, we showed that exposing postnatal day (PND) 7 rats to isoflurane diminishes hippocampal neurogenesis, inhibits dendritic spine development and synaptic plasticity, and impairs learning and memory function. These results suggest that the disruption of PDZ interactions and PDZ domain-mediated synaptic function may play important roles in the pathogenesis of early anesthetic exposure-produced long-term cognitive impairment. We hypothesize that early exposure of neonatal rats to inhaled anesthetics inhibits neurogenesis and interferes with synaptogenesis by disrupting synaptic PDZ interactions and PDZ domain-mediated synaptic function in the developing hippocampus, thereby producing long-term neurocognitive dysfunction. To address this hypothesis, we will determine whether synaptic PDZ interactions and PDZ domain-mediated synaptic function contribute to the mechanism underlying isoflurane suppression of neurogenesis and inhibition of synaptogenesis (Aim 1); we will determine the cell biological effects of inhaled anesthetic isoflurane-mediated PDZ domain disruption in developing hippocampal neurons in vitro (Am 2); we will further determine whether the disruption of synaptic PDZ interactions and the impairment of PDZ domain-mediated synaptic function contributes to long-term cognitive impairment after early anesthetic exposure (Aim 3). The proposed studies will provide critical evidence to clarify whether early anesthetic exposure produces long-term cognitive impairment by inhibiting PDZ interaction-regulated hippocampal neurogenesis and synaptogenesis. The data will shed new light on the pathogenesis of neonatal anesthetic neurotoxicity. The overall goal of this proposal is to demonstrate the roles of synaptic PDZ interactions and PDZ domain-mediated synaptic function in early anesthetic exposure- produced long-term cognitive impairment.

描述（由申请人提供）：之前的临床队列研究和动物研究表明，早期接触麻醉剂是以后发展的一个重要风险因素。学习障碍。然而，潜在的分子机制尚不清楚。多项证据表明，海马神经发生和突触发生受损可能与早期麻醉暴露造成长期认知障碍的机制有关，并且突触支架蛋白 PSD-95 PDZ 结构域介导的蛋白间相互作用和突触活动参与海马神经发生和突触发生的调节。我们之前的研究表明，临床相关浓度的吸入麻醉剂会破坏 PDZ 结构域介导的蛋白质相互作用。最近，我们发现，将出生后第 7 天（PND）的大鼠暴露于异氟烷会减少海马神经发生，抑制树突棘发育和突触可塑性，并损害学习和记忆功能。这些结果表明，PDZ 相互作用和 PDZ 结构域介导的突触功能的破坏可能在早期麻醉暴露引起的长期认知障碍的发病机制中发挥重要作用。我们假设新生大鼠早期接触吸入麻醉剂会通过破坏发育中海马体中的突触 PDZ 相互作用和 PDZ 结构域介导的突触功能来抑制神经发生并干扰突触发生，从而产生长期的神经认知功能障碍。为了解决这一假设，我们将确定突触 PDZ 相互作用和 PDZ 结构域介导的突触功能是否有助于异氟烷抑制神经发生和突触发生的机制（目标 1）；我们将确定吸入麻醉剂异氟烷介导的 PDZ 结构域破坏对体外发育的海马神经元的细胞生物学效应 (Am 2)；我们将进一步确定突触 PDZ 相互作用的破坏和 PDZ 结构域介导的突触功能的损害是否会导致早期麻醉暴露后的长期认知障碍（目标 3）。拟议的研究将提供关键证据来阐明早期麻醉暴露是否通过抑制 PDZ 相互作用调节的海马神经发生和突触发生而产生长期认知障碍。这些数据将为新生儿麻醉神经毒性的发病机制提供新的线索。该提案的总体目标是证明突触 PDZ 相互作用和 PDZ 结构域介导的突触功能在早期麻醉暴露产生的长期认知障碍中的作用。