A Dendritic Substrate for Fast-Acting Antidepressant Action

项目总结 我们的长期目标是了解额叶皮质树突的结构和功能是如何 受到压力和抗抑郁药物的影响。相当多的证据表明，快速反应的行动 像氯胺酮这样的抗抑郁药物依赖于额叶皮质的突触可塑性。一种重要的配料 可塑性是指钙离子流入树突棘。然而，到目前为止，经验数据详细说明了抗抑郁药物 可能调节体内树突棘中的钙水平是缺乏的。在初步研究中，我们使用了亚细胞- 分辨率双光子显微镜观察内侧树突棘内的局部钙瞬变 活体小鼠的额叶皮质。我们发现，服用速效抗抑郁药氯胺酮 导致顶端树突棘中钙信号的急性升高，这是由于树突状细胞的抑制 抑制力。根据初步结果和先前的研究，我们假设增强的 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 确定应激和氯胺酮对突触钙信号的交互作用(目标1)。我们会追踪 同一树突棘中的形态和钙信号，以询问钙的升高是否先于结构 重塑(目标2)。我们将确定接受来自特定远程传入区域的输入的脊髓是否 有选择地瞄准(目标3)。综上所述，这些结果有望为深入了解糖尿病的生物学基础提供依据。 氯胺酮的作用。由于钙是额叶皮质突触可塑性的重要检查点，描绘了 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。

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.