State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Department of Physiology, School of Medicine, Jinan University, Guangzhou, China.
Biol Psychiatry. 2025 Jan 1;97(1):41-53. doi: 10.1016/j.biopsych.2024.04.013. Epub 2024 Apr 26.
Neuronal activity is the basis of information encoding and processing in the brain. During neuronal activation, intracellular ATP (adenosine triphosphate) is generated to meet the high-energy demands. Simultaneously, ATP is secreted, increasing the extracellular ATP concentration and acting as a homeostatic messenger that mediates cell-cell communication to prevent aberrant hyperexcitability of the nervous system. In addition to the confined release and fast synaptic signaling of classic neurotransmitters within synaptic clefts, ATP can be released by all brain cells, diffuses widely, and targets different types of purinergic receptors on neurons and glial cells, making it possible to orchestrate brain neuronal activity and participate in various physiological processes, such as sleep and wakefulness, learning and memory, and feeding. Dysregulation of extracellular ATP leads to a destabilizing effect on the neural network, as found in the etiopathology of many psychiatric diseases, including depression, anxiety, schizophrenia, and autism spectrum disorder. In this review, we summarize advances in the understanding of the mechanisms by which extracellular ATP serves as an intercellular signaling molecule to regulate neural activity, with a focus on how it maintains the homeostasis of neural networks. In particular, we also focus on neural activity issues that result from dysregulation of extracellular ATP and propose that aberrant levels of extracellular ATP may play a role in the etiopathology of some psychiatric diseases, highlighting the potential therapeutic targets of ATP signaling in the treatment of these psychiatric diseases. Finally, we suggest potential avenues to further elucidate the role of extracellular ATP in intercellular communication and psychiatric diseases.
神经元活动是大脑信息编码和处理的基础。在神经元激活过程中，细胞内会产生 ATP（三磷酸腺苷）以满足高能量需求。同时，ATP 被分泌出来，增加细胞外 ATP 浓度，并作为一种体内平衡信使，介导细胞间通讯，以防止神经系统异常过度兴奋。除了突触小泡内经典神经递质的有限释放和快速突触信号传递外，ATP 还可以由所有脑细胞释放，广泛扩散，并作用于神经元和神经胶质细胞上的不同类型嘌呤能受体，从而协调大脑神经元活动并参与各种生理过程，如睡眠和觉醒、学习和记忆以及进食。细胞外 ATP 的失调会对神经网络产生不稳定的影响，这在许多精神疾病的发病机制中都有发现，包括抑郁症、焦虑症、精神分裂症和自闭症谱系障碍等。在这篇综述中，我们总结了细胞外 ATP 作为细胞间信号分子调节神经活动的机制方面的研究进展，重点关注其如何维持神经网络的体内平衡。特别是，我们还关注了由于细胞外 ATP 失调导致的神经活动问题，并提出异常水平的细胞外 ATP 可能在某些精神疾病的发病机制中发挥作用，强调了 ATP 信号在这些精神疾病治疗中的潜在治疗靶点。最后，我们提出了进一步阐明细胞外 ATP 在细胞间通讯和精神疾病中的作用的潜在途径。
