Microglia cytoarchitecture in the brain of adenosine A_2A receptor knockout mice: Brain region and sex specificities

Abstract

Microglia cells exert a critical role in brain development, mainly supported by their immune functions, which predicts an impact on the genesis of psychiatric disorders. In fact, microglia stress during gestation is, for instance, associated with chronic anxiety and cognitive deficits accompanied by long‐lasting, region‐ and sex‐specific changes in microglia morphology. We recently reported that the pattern of microglia morphologic plasticity, which is sex‐determined, impacts on anxious‐like behaviour and cognition. We also reported that the pharmacologic blockade of adenosine A2A receptors (A2AR) is able to reshape microglia morphology, in a sex‐specific manner and with behavioural sequelae. In order to better understand the role of A2AR in the sex differentiation of microglia, we now compared their morphology in wild‐type and A2AR knockout male and female C57BL/6 mice in two cardinal brain regions implicated in anxiety‐like behaviour and cognition, the prefrontal cortex (PFC) and the dorsal hippocampus (dHIP). We report interregional differences between PFC and dHIP in a sex‐specific manner: while males presented more complex microglia in the dHIP, microglia from females had a more complex morphology in the PFC. Surprisingly, the genetic deletion of A2AR did not alter these sex differences, but promoted the exclusive remodelling (increase in complexity) in PFC microglia from females. These findings further support the existence of a heterogeneous microglial network, distinct between sexes and brain regions, and help characterizing the role of A2AR in the sex‐ and brain region‐specific morphologic differentiation of microglia.

Resilience to stress and sex-specific remodeling of microglia and neuronal morphology in a rat model of anxiety and anhedonia

“…These differences between sexes probably result from the when subjected to stress conditions in brain regions with a sex-dependent complexity typified by more complex cells in females than in males ( Schwarz et al, 2012 ; Lenz and McCarthy, 2015 ). Moreover, the existence of sex- and brain region-specific morphologic differentiation of microglia must be conserved among species, since we observed the same dichotomy in a mice model ( Simoes-Henriques et al, 2019 ).…”

Advantages in Wound Healing Process in Female Mice Require Upregulation A2A-Mediated Angiogenesis under the Stimulation of 17β-Estradiol

“…In line with this observation, specific differences such as higher macrophage infiltration [1] or collagen (type I and III) synthesis [28] in the healing area were found in females when compared to male mice. Under this complexity, sex dimorphism in some cardiovascular functions [25] or the brain maturation process [26] has already been described in A 2A KO mice. We contribute to those findings by indicating that sex dimorphism may also be present during the wound healing process and tissue perfusion.…”

“…Under this complexity, sex dimorphism in some cardiovascular functions [ 25 ] or the brain maturation process [ 26 ] has already been described in A 2A KO mice. We contribute to those findings by indicating that sex dimorphism may also be present during the wound healing process and tissue perfusion.…”

“…Indeed, 17β-estradiol upregulates the mRNA levels of A 2A in a dose-dependent manner in the human cancer cell line MCF-7 [ 24 ]. Complementary to this in vitro evidence, it has been shown that mice lacking A 2A receptors exhibited sex dimorphism in many physiological processes including heart rate, temperature, locomotion activities, oxygen demand [ 25 ], and maturation of the microglia in the brain [ 26 ], in which female A 2A KO mice were less negatively affected than male A 2A KO.…”

Crosstalk Between ATP-P2X7 and Adenosine A2A Receptors Controlling Neuroinflammation in Rats Subject to Repeated Restraint Stress

“…This indicates that these two, so far considered independent, arms of the purinergic system (Agostinho et al, 2020), operated by ATP-P 2 R and by adenosine-P 1 R might actually cooperate to control adaptative brain function. Importantly, this proofof-concept, so far only confirmed to occur in male rats (selected to cope with the ''3R'' guidelines), still needs to be extended to female rats, an issue of particular importance since there are gender differences in the A 2A R modulation of microglia and neuroinflammatory-like responses in rodents (Caetano et al, 2017;Simões-Henriques et al, 2020).…”