High, in Contrast to Low Levels of Acute Stress Induce Depressive-like Behavior by Involving Astrocytic, in Addition to Microglial P2X7 Receptors in the Rodent Hippocampus

Abstract

Extracellular adenosine 5′-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.

Increased Synaptic ATP Release and CD73-Mediated Formation of Extracellular Adenosine in the Control of Behavioral and Electrophysiological Modifications Caused by Chronic Stress

“…On one hand, it has been established that the blockade of A 2A R prevents moods dysfunction upon repeated stress, − in accordance with the association of A 2A R polymorphisms with the incidence of major depression . In parallel, there is robust evidence that P 2X7 R antagonism also prevents mood dysfunction upon repeated stress, − also in accordance with the association of P 2X7 R polymorphisms with the incidence of major depression (reviewed in ref ). This implies an overfunction of purinergic A 2A R and P 2X7 R, which apparently contrasts with the proposed antidepressant role of ATP based on the reported decreased ATP levels associated with depression. − This is particularly surprising since ATP is a danger signal in the brain (reviewed in ref ), and there is an increased ATP release in different brain diseases, ,,, in particular in synapses that are particularly affected at the onset of depressive conditions (reviewed in ref ).…”

Electroacupuncture prevents astrocyte atrophy to alleviate depression

“…The sucrose preference test is a reward-based test and a measure of anhedonia, as previously described (Zhao et al, 2022). The mice were singly caged for 3 days and given two 50 mL bottles containing water or water-based 1% sucrose solution (wt/vol), respectively.…”

“…The FST was performed as previously described (Zhao et al, 2022), in a clear glass cylinder filled with water (temperature, 23 -25 o C); cylinder's dimensions were: height, 30 cm; diameter, 20 cm; water level, 15 cm. Mice were gently placed in the tanks.…”

“…The open field test was performed as previously described (Zhao et al, 2022). The apparatus consisted of a rectangular chamber (50 × 50 × 50 cm) made of white, high density, non-porous plastic.…”

Extracellular Vesicles and the Stress System

“…Frank et al [171] proposed that both GCs and NE prime microglia. Zhao et al [352] showed that high, but not low levels of acute stress, as well as chronic stress, induce a depressive-like behavior, through the action of ATP on astrocytic and microglial P2X7 receptors. Therefore, one should consider that several neuropeptides and other molecules and their receptors may also mediate the effects of stress on astrocytes and microglia.…”