Extracellular adenosine 50-triphosphate (ATP) in the brain is suggested to be an etiological
factor of major depressive disorder (MDD). It has been assumed that stress-released ATP stimulates
P2X7 receptors (Rs) at the microglia, thereby causing neuroinflammation; however, other central nervous
system (CNS) cell types such as astrocytes also possess P2X7Rs. In order to elucidate the possible
involvement of the MDD-relevant hippocampal astrocytes in the development of a depressive-like
state, we used various behavioral tests (tail suspension test [TST], forced swim test [FST], restraint
stress, inescapable foot shock, unpredictable chronic mild stress [UCMS]), as well as fluorescence
immunohistochemistry, and patch-clamp electrophysiology in wild-type (WT) and genetically manipulated
rodents. The TST and FST resulted in learned helplessness manifested as a prolongation
of the immobility time, while inescapable foot shock caused lower sucrose consumption as a sign
of anhedonia. We confirmed the participation of P2X7Rs in the development of the depressive-like
behaviors in all forms of acute (TST, FST, foot shock) and chronic stress (UCMS) in the rodent models
used. Further, pharmacological agonists and antagonists acted in a different manner in rats and
mice due to their diverse potencies at the respective receptor orthologs. In hippocampal slices of
mice and rats, only foot shock increased the current responses to locally applied dibenzoyl-ATP
(Bz-ATP) in CA1 astrocytes; in contrast, TST and restraint depressed these responses. Following
stressful stimuli, immunohistochemistry demonstrated an increased co-localization of P2X7Rs with
a microglial marker, but no change in co-localization with an astroglial marker. Pharmacological
damage to the microglia and astroglia has proven the significance of the microglia for mediating
all types of depression-like behavioral reactions, while the astroglia participated only in reactions
induced by strong stressors, such as foot shock. Because, in addition to acute stressors, their chronic
counterparts induce a depressive-like state in rodents via P2X7R activation, we suggest that our data
may have relevance for the etiology of MDD in humans.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:89098 |
| Date | 17 January 2024 |
| Creators | Zhao, Ya-Fei, Ren, Wen-Jing, Zhang, Ying, He, Jin-Rong, Yin, Hai-Yan, Liao, Yang, Rubini, Patrizia, Deussing, Jan M., Verkhratsky, Alexei, Yuan, Zeng-Qiang, Illes, Peter, Tang, Yong |
| Publisher | MDPI |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 1904 |
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