Astrocyte-derived ATP modulates depressive-like behaviors

Citation metadata

Date: June 2013
From: Nature Medicine(Vol. 19, Issue 6)
Publisher: Nature Publishing Group
Document Type: Report
Length: 6,645 words
Lexile Measure: 1390L

Document controls

Main content

Article Preview :

Major depressive disorder (MDD) is a cause of disability that affects approximately 16% of the world's population (1); however, little is known regarding the underlying biology of this disorder. Animal studies, postmortem brain analyses and imaging studies of patients with depression have implicated glial dysfunction in MDD pathophysiology (2-7). However, the molecular mechanisms through which astrocytes modulate depressive behaviors are largely uncharacterized. Here, we identified ATP as a key factor involved in astrocytic modulation of depressive-like behavior in adult mice. We observed low ATP abundance in the brains of mice that were susceptible to chronic social defeat. Furthermore, we found that the administration of ATP induced a rapid antidepressant-like effect in these mice. Both a lack of inositol 1,4,5-trisphosphate receptor type 2 and transgenic blockage of vesicular gliotransmission induced deficiencies in astrocytic ATP release, causing depressive-like behaviors that could be rescued via the administration of ATP. Using transgenic mice that express a [G.sub.q] G protein-coupled receptor only in astrocytes to enable selective activation of astrocytic [Ca.sup.2+] signaling, we found that stimulating endogenous ATP release from astrocytes induced antidepressant-like effects in mouse models of depression. Moreover, we found that P2X2 receptors in the medial prefrontal cortex mediated the antidepressant-like effects of ATP. These results highlight astrocytic ATP release as a biological mechanism of MDD.

The chronic social defeat stress (CSDS) model mimics several psychopathological dimensions of depression, and adult C57BL/6J mice that are subjected to CSDS can be separated into susceptible and unsusceptible subpopulations (8), (9) (Supplementary Fig. 1a and Supplementary Methods). To characterize the neurobiological mechanisms that underlie astrocyte dysfunction in depression, we analyzed the amounts of peptide trophic factors and neurotransmitters that are known to be secreted by astrocytes in the prefrontal cortex (PFC) and hippocampus, two candidate sites for impaired functions in MDD (6), (10), in mice subjected to CSDS (Supplementary Fig. 1b). Notably, the concentration of ATP was lower in the artificial cerebral spinal fluid (ACSF) from PFC or hippocampal slices that were isolated from susceptible but not unsusceptible mice when compared with nondefeated control mice (Fig. 1a), suggesting an ATP deficiency in the brains of mice that are sensitive to CSDS. To determine whether ATP deficiency underlies acute behavioral despair, we used the forced swimming test (FST). We found that ATP amounts were lower in the brains of mice subjected to a 6-min FST when compared with undisturbed control mice (Fig. 1b). Further in vivo microdialysis experiments demonstrated that ATP concentrations in the interstitial fluid were lower in the PFC and hippocampus of the mice that were susceptible to CSDS (Fig. 1c). Together, these results suggest that reduced levels of ATP in the brain underlie depressive-like behaviors.

To test whether ATP could induce an antidepressant-like effect, we employed the FST (Supplementary Fig. 2a). A physiological concentration of ATP (25 [mu]M, lateral intracerebroventricular (i.c.v.) infusion) (11) decreased the total duration of immobility in adult C57BL6/J mice. Moreover, ATP-[gamma]-S, a nonhydrolyzable ATP analog, dramatically decreased the total duration of immobility, excluding the possible contribution of ATP hydrolysis products....

Source Citation

Source Citation   

Gale Document Number: GALE|A334606590