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A Dendritic Substrate for Fast-Acting Antidepressant Action

具有快速抗抑郁作用的树突状基质

基本信息

批准号：
10623145
负责人：
CHUN-HAY ALEX KWAN
金额：
$ 50.17万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-20 至 2025-04-30
项目状态：
未结题

项目摘要

PROJECT SUMMARY Our long-term goal is to understand how the structure and function of dendrites in the frontal cortex are affected by stress and antidepressants. Considerable evidence indicates that the action of fast-acting antidepressants such as ketamine relies on synaptic plasticity in the frontal cortex. An essential ingredient for plasticity is calcium influx in dendritic spines. However, to date, empirical data detailing how antidepressants may modulate calcium levels in dendritic spines in vivo are lacking. In preliminary studies, we used subcellular- resolution two-photon microscopy to visualize localized calcium transients in dendritic spines in the medial frontal cortex of the mouse in vivo. We found that the administration of the fast-acting antidepressant ketamine leads to an acute elevation of calcium signals in apical dendritic spines, due to a suppression of dendritic inhibition. On the basis of the preliminary results and prior research, we hypothesize that the enhanced synaptic calcium signal is a necessary step towards ketamine’s antidepressant action. In this project, we will determine the interactive effects of stress and ketamine on synaptic calcium signals (Aim 1). We will track morphology and calcium signals in the same dendritic spines to ask if the calcium elevations precede structural remodeling (Aim 2). We will determine if spines receiving inputs from specific long-range afferent regions are selectively targeted (Aim 3). Together, the results are expected to provide insights into the biological basis of ketamine’s action. As calcium is an essential checkpoint for synaptic plasticity in the frontal cortex, delineating its role in antidepressant action will accelerate the evaluation of candidate compounds and the development of more targeted treatments.

项目概要我们的长期目标是了解额叶皮层树突的结构和功能如何受到压力和抗抑郁药物的影响。大量证据表明，速效药物的作用氯胺酮等抗抑郁药依赖于额叶皮层的突触可塑性。的重要成分可塑性是树突棘中的钙流入。然而，迄今为止，经验数据详细说明了抗抑郁药如何体内缺乏可能调节树突棘钙水平的药物。在初步研究中，我们使用了亚细胞分辨率双光子显微镜可观察内侧树突棘中的局部钙瞬变小鼠体内额叶皮质。我们发现服用速效抗抑郁药氯胺酮由于树突棘的抑制，导致顶端树突棘中钙信号的急剧升高抑制。根据初步结果和先前研究，我们假设增强突触钙信号是氯胺酮抗抑郁作用的必要步骤。在这个项目中，我们将确定压力和氯胺酮对突触钙信号的交互影响（目标 1）。我们将追踪同一树突棘中的形态和钙信号，以询问钙升高是否先于结构升高重塑（目标 2）。我们将确定从特定远程传入区域接收输入的棘是否是有选择性地瞄准（目标 3）。总之，这些结果预计将提供对生物学基础的见解氯胺酮的作用。由于钙是额叶皮层突触可塑性的重要检查点，因此它在抗抑郁作用中的作用将加速候选化合物的评估和开发更有针对性的治疗。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A database and deep learning toolbox for noise-optimized, generalized spike inference from calcium imaging.

DOI：
10.1038/s41593-021-00895-5
发表时间：
2021-09
期刊：
Nature neuroscience
影响因子：
25
作者：
Rupprecht P;Carta S;Hoffmann A;Echizen M;Blot A;Kwan AC;Dan Y;Hofer SB;Kitamura K;Helmchen F;Friedrich RW
通讯作者：
Friedrich RW

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