Department of Neurobiology, Harvard Medical School, Boston, MA, 02115, USA.
Mol Psychiatry. 2024 Nov;29(11):3680-3693. doi: 10.1038/s41380-024-02608-3. Epub 2024 May 24.
A wealth of neuromodulatory transmitters regulate synaptic circuits in the brain. Their mode of signaling, often called volume transmission, differs from classical synaptic transmission in important ways. In synaptic transmission, vesicles rapidly fuse in response to action potentials and release their transmitter content. The transmitters are then sensed by nearby receptors on select target cells with minimal delay. Signal transmission is restricted to synaptic contacts and typically occurs within ~1 ms. Volume transmission doesn't rely on synaptic contact sites and is the main mode of monoamines and neuropeptides, important neuromodulators in the brain. It is less precise than synaptic transmission, and the underlying molecular mechanisms and spatiotemporal scales are often not well understood. Here, we review literature on mechanisms of volume transmission and raise scientific questions that should be addressed in the years ahead. We define five domains by which volume transmission systems can differ from synaptic transmission and from one another. These domains are (1) innervation patterns and firing properties, (2) transmitter synthesis and loading into different types of vesicles, (3) architecture and distribution of release sites, (4) transmitter diffusion, degradation, and reuptake, and (5) receptor types and their positioning on target cells. We discuss these five domains for dopamine, a well-studied monoamine, and then compare the literature on dopamine with that on norepinephrine and serotonin. We include assessments of neuropeptide signaling and of central acetylcholine transmission. Through this review, we provide a molecular and cellular framework for volume transmission. This mechanistic knowledge is essential to define how neuromodulatory systems control behavior in health and disease and to understand how they are modulated by medical treatments and by drugs of abuse.
大量的神经调质递质调节大脑中的突触回路。它们的信号传递方式，通常被称为容积传递，在许多重要方面与经典的突触传递不同。在突触传递中，囊泡会迅速响应动作电位融合并释放其递质内容物。然后，递质被附近的受体以最小的延迟感知，这些受体位于特定的靶细胞上。信号传递仅限于突触接触，通常发生在~1ms 内。容积传递不依赖于突触接触位点，是单胺类和神经肽等脑内重要神经调质的主要传递方式。它不如突触传递精确，其潜在的分子机制和时空尺度通常还不太清楚。在这里，我们回顾了关于容积传递机制的文献，并提出了在未来几年应该解决的科学问题。我们通过五个方面来定义容积传递系统与突触传递以及彼此之间的不同之处。这些方面是（1）神经支配模式和放电特性，（2）递质的合成和装入不同类型的囊泡，（3）释放位点的结构和分布，（4）递质的扩散、降解和再摄取，以及（5）受体类型及其在靶细胞上的定位。我们讨论了多巴胺这个研究得很好的单胺作为这五个方面的一个例子，然后将多巴胺的文献与去甲肾上腺素和 5-羟色胺的文献进行了比较。我们还包括了对神经肽信号传递和中枢乙酰胆碱传递的评估。通过这篇综述，我们提供了一个容积传递的分子和细胞框架。这种机制知识对于定义神经调质系统如何在健康和疾病中控制行为以及理解它们如何被医学治疗和滥用药物所调节是必不可少的。
