Summary: New research indicates that reduced ATP signaling in the dorsal hippocampus contributes directly to both depression- and anxiety-like behaviors. In male mice exposed to chronic stress, extracellular ATP and the ATP-release protein connexin 43 (Cx43) were significantly decreased.
When connexin 43 was experimentally reduced or deleted in hippocampal astrocytes, mice developed depression- and anxiety-like behaviors even without prior stress, confirming a causal role. Restoring connexin 43 expression recovered ATP signaling and alleviated behavioral symptoms, highlighting a shared molecular mechanism and a promising therapeutic target for co-occurring depression and anxiety.
Key Facts:
- Shared mechanism: Reduced ATP release from the dorsal hippocampus drives both depressive- and anxiety-like behaviors.
- Connexin 43 is central: Loss or suppression of astrocytic Cx43 is sufficient to produce these behavioral changes.
- Reversal is possible: Reintroducing Cx43 and restoring ATP levels reverses behavioral deficits in stressed mice.
Source: SfN
In a new Journal of Neuroscience paper, Tian-Ming Gao and colleagues at Southern Medical University investigated how adenosine triphosphate (ATP) signaling in the hippocampus relates to depression and anxiety using male mice.
ATP is widely known as the cell’s energy currency, but it also functions as a signaling molecule that shapes neuronal and glial communication. Gao and coauthors focused on extracellular ATP signaling in the dorsal hippocampus, a brain region implicated in mood regulation and stress responses.
Their experiments showed that male mice susceptible to chronic social defeat stress had lower extracellular ATP levels and reduced expression of connexin 43 in the dorsal hippocampus, while the ventral hippocampus did not show the same changes. Connexin 43 is a protein that forms channels allowing molecules like ATP to be released from astrocytes into the extracellular space.
To test causality, the team selectively knocked down or conditionally deleted Cx43 in hippocampal astrocytes. This targeted reduction of connexin 43 was sufficient to lower extracellular ATP and induce behaviors that model core symptoms of depression and anxiety. By contrast, deleting Cx43 in neurons did not produce these behavioral effects, pointing specifically to an astrocyte-driven mechanism.
Complementary experiments showed that supplementing extracellular ATP with a stable ATP analog reversed behavioral deficits caused by Cx43 loss. Moreover, combining Cx43 overexpression with inhibition of ATP-degrading enzymes raised ATP levels in the dorsal hippocampus and improved behavioral outcomes in stressed mice. Together, these findings indicate that astrocytic Cx43 controls ATP release and that ATP signaling is a crucial regulator of mood-related behaviors.
Gao summarizes the significance: this work provides direct evidence that deficient ATP release from dorsal hippocampal astrocytes drives both depressive- and anxiety-like behaviors, revealing a common molecular pathway underlying these comorbid conditions. The authors emphasize that targeting Cx43-mediated ATP signaling could offer a new avenue for therapies aimed at co-occurring depression and anxiety.
The study focused on adult male mice; the authors report plans to include both sexes in future research to determine whether the same ATP–Cx43 mechanism operates in females as well.
Key Questions Answered:
A: Reduced ATP release from astrocytes in the dorsal hippocampus directly contributes to depressive- and anxiety-like behaviors in mice.
A: Loss or suppression of astrocytic connexin 43 impairs ATP release, which triggers behavioral symptoms associated with depression and anxiety.
A: Yes. Reintroducing connexin 43 and boosting extracellular ATP levels normalized ATP signaling and improved behavior in stressed mice.
Editorial Notes:
- Edited by a Neuroscience News editor.
- Original journal paper reviewed in full by editorial staff.
- Additional context added by the newsroom.
About this depression and neuroscience research news
Author: SfN Media ([email protected])
Source: SfN
Contact: SfN Media – SfN
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Original Research: Closed access.
“ATP Release Deficiency Through Astrocytic Connexin 43 in the Dorsal Hippocampus Promotes Depressive- and Anxiety-like Behaviors” by Tian-Ming Gao et al., Journal of Neuroscience.
Abstract
ATP Release Deficiency Through Astrocytic Connexin 43 in the Dorsal Hippocampus Promotes Depressive- and Anxiety-like Behaviors
Depression is a widespread psychiatric disorder, and accumulating evidence implicates dysregulated extracellular ATP signaling and hippocampal dysfunction in its development. The role of ATP release and the mechanisms linking ATP signaling to both depression and anxiety, however, have not been fully established.
This study observed reduced connexin 43 (Cx43) expression and lower extracellular ATP specifically in the dorsal hippocampus of adult male mice susceptible to chronic social defeat stress. Conditional knockout or targeted knockdown of astrocytic Cx43 in the dorsal hippocampus produced depressive- and anxiety-like behaviors and decreased extracellular ATP, while neuronal Cx43 knockout had no effect. Supplementing extracellular ATP reversed behavioral deficits, and manipulating Cx43 levels altered astrocytic connectivity and morphology. Overexpression of Cx43 together with inhibition of ATP-degrading enzymes restored ATP levels and ameliorated behavioral impairments.
These results demonstrate that impaired ATP release from dorsal hippocampal astrocytes—mediated primarily by Cx43—leads to depression- and anxiety-like behaviors. The findings clarify a molecular mechanism linking ATP signaling to mood disorders and identify Cx43-mediated ATP release in the dorsal hippocampus as a potential therapeutic target for treating comorbid depression and anxiety.