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 Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China; Physiology Department and Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China.
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 Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Biol Psychiatry. 2022 Aug 1;92(3):179-192. doi: 10.1016/j.biopsych.2022.02.014. Epub 2022 Feb 22.
Depression is the most common mental illness. Mounting evidence suggests that dysregulation of extracellular ATP (adenosine triphosphate) is involved in the pathophysiology of depression. However, the cellular and neural circuit mechanisms through which ATP modulates depressive-like behavior remain elusive.
By use of ex vivo slice electrophysiology, chemogenetic manipulations, RNA interference, gene knockout, behavioral testing, and two depression mouse models, one induced by chronic social defeat stress and one caused by a IP3R2-null mutation, we systematically investigated the cellular and neural circuit mechanisms underlying ATP deficiency-induced depressive-like behavior.
Deficiency of extracellular ATP in both defeated susceptible mice and IP3R2-null mutation mice led to reduced GABAergic (gamma-aminobutyric acidergic) inhibition and elevated excitability in lateral habenula-projecting, but not dorsal raphe-projecting, medial prefrontal cortex (mPFC) neurons. Furthermore, the P2X2 receptor in GABAergic interneurons mediated ATP modulation of lateral habenula-projecting mPFC neurons and depressive-like behavior. Remarkably, chemogenetic activation of the mPFC-lateral habenula pathway induced depressive-like behavior in C57BL/6J mice, while inhibition of this pathway was sufficient to alleviate the behavioral impairment in both defeated susceptible and IP3R2-null mutant mice.
Overall, our study provides compelling evidence that ATP level in the mPFC is critically involved in regulating depressive-like behavior in a pathway-specific manner. These results shed new light on the mechanisms underlying depression and the antidepressant effect of ATP.
抑郁症是最常见的精神疾病。越来越多的证据表明，细胞外三磷酸腺苷（ATP）的失调与抑郁症的病理生理学有关。然而，ATP 调节抑郁样行为的细胞和神经回路机制仍不清楚。
通过使用离体脑片电生理学、化学遗传学操作、RNA 干扰、基因敲除、行为测试以及两种抑郁小鼠模型，一种由慢性社交挫败应激诱导，另一种由 IP3R2 缺失突变引起，我们系统地研究了 ATP 缺乏诱导的抑郁样行为的细胞和神经回路机制。
在易受攻击的被击败小鼠和 IP3R2 缺失突变小鼠中，细胞外 ATP 的缺乏导致外侧缰核投射但不包括中缝背核投射的内侧前额叶皮层（mPFC）神经元中 GABA 能（γ-氨基丁酸能）抑制减少和兴奋性升高。此外，GABA 能中间神经元中的 P2X2 受体介导了 ATP 对外侧缰核投射 mPFC 神经元和抑郁样行为的调节。值得注意的是，mPFC-外侧缰核通路的化学遗传学激活在 C57BL/6J 小鼠中引起了抑郁样行为，而抑制该通路足以缓解易受攻击的被击败小鼠和 IP3R2 缺失突变小鼠的行为障碍。
总的来说，我们的研究提供了令人信服的证据，表明 mPFC 中的 ATP 水平以特定通路的方式参与调节抑郁样行为。这些结果为抑郁症的发病机制和 ATP 的抗抑郁作用提供了新的见解。
