Researchers report that reduced ATP signaling in the dorsal hippocampus of male mice, driven by changes in the protein connexin 43, can trigger both depression- and anxiety-like behaviors. The study, published in The Journal of Neuroscience, finds that chronic stress lowers extracellular ATP and connexin 43 levels, that experimentally reducing the protein induces similar behaviors even without stress, and that restoring it in stressed animals improves behavioral signs of distress.
A research team led by Tian-Ming Gao at Southern Medical University investigated how adenosine triphosphate (ATP) signaling influences emotion-related behavior in adult male mice, focusing on the dorsal hippocampus. This brain region is involved in memory and stress responses and has been strongly implicated in mood disorders, in part because it is sensitive to prolonged stress and changes in emotional regulation.
ATP is best known as the cell's main energy carrier, but it also acts as a chemical messenger that helps neurons and other brain cells communicate. Because healthy communication between brain cells is essential for regulating mood, Gao's group centered their work on how ATP is released and regulated in the dorsal hippocampus, according to a summary from the Society for Neuroscience.
In mice exposed to chronic social defeat stress, the researchers found that animals susceptible to developing depression- and anxiety-like behaviors had reduced extracellular ATP levels in the dorsal hippocampus, along with lower expression of connexin 43. Connexin 43 forms channels in astrocytes that help release ATP into the space outside cells, making it a key regulator of local brain energy signaling.
To isolate the role of ATP release from stress itself, the team used conditional genetic tools to decrease or delete connexin 43 specifically in astrocytes in the dorsal hippocampus of otherwise non-stressed mice. This manipulation led to lower extracellular ATP and induced both depressive- and anxiety-like behaviors, while similar connexin 43 deletion in neurons did not produce these behavioral changes, the authors report in The Journal of Neuroscience.
The study also showed that supplementing stressed, susceptible mice with a stable ATP analogue (ATPγS) could reverse some behavioral deficits, and that boosting connexin 43 in dorsal hippocampal astrocytes while limiting ATP breakdown restored ATP levels and improved mood-related behaviors. Together, these experiments indicate that deficient ATP release from astrocytes in the dorsal hippocampus can causally drive depression- and anxiety-like behaviors in this mouse model.
Gao said in a news release that "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]." The work helps explain why depression and anxiety frequently co-occur and points to astrocytic connexin 43 and ATP signaling as potential therapeutic targets for treating these comorbid disorders.
According to the Society for Neuroscience and related coverage by outlets including ScienceDaily and Medical Xpress, the researchers now plan to extend the work to include both male and female mice in future experiments to test whether the same mechanisms operate across sexes.
