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Astrocyte-derived ATP modulates depressive-like behaviors.
Xiong Cao1, Liang-Ping Li, Qian Wang
1Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Nature Medicine
|May 7, 2013
Summary
Adenosine triphosphate (ATP) released by astrocytes rapidly reduces depressive behaviors in mice. This discovery highlights astrocytic ATP signaling as a potential therapeutic target for major depressive disorder (MDD).
Area of Science:
- Neuroscience
- Molecular Biology
- Psychiatry
Background:
- Major depressive disorder (MDD) is a leading cause of global disability, yet its biological underpinnings remain poorly understood.
- Glial dysfunction, particularly involving astrocytes, is implicated in MDD pathophysiology, but specific molecular mechanisms are largely uncharacterized.
- Astrocytes play crucial roles in brain function, including neurotransmission and support for neurons.
Purpose of the Study:
- To investigate the role of astrocytes in modulating depressive-like behaviors.
- To identify molecular factors involved in astrocytic modulation of depression.
- To explore potential therapeutic targets for MDD based on astrocytic function.
Main Methods:
- Utilized mouse models of depression, including chronic social defeat stress.
- Measured adenosine triphosphate (ATP) levels in mouse brains.
- Administered ATP and employed genetic manipulations (inositol 1,4,5-trisphosphate receptor type 2 deficiency, transgenic blockage of gliotransmission, astrocyte-specific Gq-GPCR activation) to assess astrocytic ATP release and its behavioral effects.
- Investigated the role of P2X2 receptors in the medial prefrontal cortex.
Main Results:
- Reduced ATP abundance was observed in the brains of mice susceptible to chronic social defeat.
- Administration of ATP rapidly induced antidepressant-like effects in these mice.
- Deficiencies in astrocytic ATP release, caused by genetic alterations, led to depressive-like behaviors that were rescued by ATP administration.
- Stimulating endogenous astrocytic ATP release via astrocyte-specific Ca(2+) signaling activation produced antidepressant-like effects.
- P2X2 receptors in the medial prefrontal cortex were identified as mediators of ATP's antidepressant-like effects.
Conclusions:
- Astrocytic ATP release is a key mechanism modulating depressive-like behaviors in mice.
- ATP acts as a rapid antidepressant, suggesting its potential as a therapeutic agent for MDD.
- Targeting astrocytic ATP signaling pathways offers a novel biological strategy for treating major depressive disorder.
