Scientists found that reduced ATP signaling in the hippocampus can trigger both depression and anxiety in mice.
Lower ATP levels and a drop in connexin 43 expression appeared to make stressed animals more vulnerable. Manipulating this protein alone was enough to produce mood-related symptoms, while restoring it reversed them.
ATP Signaling and Mood Disorders
In a new JNeurosci publication, Tian-Ming Gao and colleagues at Southern Medical University investigated how adenosine triphosphate (ATP) signaling contributes to depression and anxiety in male mice. ATP is widely known as a source of cellular energy, but it also plays an important role in helping neurons communicate. The team centered their work on ATP activity in the hippocampus, a brain region that has been closely linked to depression.
Stress, ATP Loss, and Connexin 43
Male mice that were more prone to developing depressive- and anxiety-like behaviors after prolonged stress showed lower ATP levels and decreased expression of a protein that supports ATP release (connexin 43). When the researchers genetically reduced or removed connexin 43 in ATP-releasing cells in a separate group of mice, the animals displayed similar depressive- and anxiety-like behaviors and experienced additional drops in ATP. Bringing both lines of evidence together, the team found that reintroducing normal levels of connexin 43 in the hippocampus of stressed mice restored ATP levels and improved their behavior.
A Shared Biological Pathway
According to Gao, “This is the first direct evidence that deficient ATP release in [a region of the] hippocampus drives both depressive- and anxiety-like behaviors, revealing a shared molecular pathway [for these conditions].” He notes that the connection between connexin 43 and this pathway may offer a promising target for treating depression and anxiety when they appear together. The researchers also plan to include both male and female mice in future studies.
Reference: “ATP release deficiency through astrocytic connexin 43 in the dorsal hippocampus promotes depressive- and anxiety-like behaviors” by Meng-Ling Wang, Jian Hu, Yue-Xin Wang, Xiao-Tong Lian, Yun-Long Song, Ding-Yu Wu, Jia-Yue Du, Hao Li, Xing-Xing Xiong, Zi-Ming Li, Jing-Ting Li, Yun-Shu Wang, Jia-Yu Hu, Xiao-Wen Li, Jian-Ming Yang, Xiang-Dong Sun, Yi-Hua Chen and Tian-Ming Gao, 23 November 2025, Journal of Neuroscience.
DOI: 10.1523/JNEUROSCI.1063-25.2025
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