Region‐specific control of microglia by adenosine A_2A receptors: uncoupling anxiety and associated cognitive deficits in female rats

Abstract

Epidemiologic studies have provided compelling evidence that prenatal stress, through excessive maternal glucocorticoids exposure, is associated with psychiatric disorders later in life. We have recently reported that anxiety associated with prenatal exposure to dexamethasone (DEX, a synthetic glucocorticoid) correlates with a gender‐specific remodeling of microglia in the medial prefrontal cortex (mPFC), a core brain region in anxiety‐related disorders. Gender differences in microglia morphology, the higher prevalence of anxiety in women and the negative impact of anxiety in cognition, led us to specifically evaluate cognitive behavior and associated circuits (namely mPFC‐dorsal hippocampus, dHIP), as well as microglia morphology in female rats prenatally exposed to dexamethasone (in utero DEX, iuDEX). We report that iuDEX impaired recognition memory and deteriorated neuronal synchronization between mPFC and dHIP. These functional deficits are paralleled by microglia hyper‐ramification in the dHIP and decreased ramification in the mPFC, showing a heterogeneous remodeling of microglia morphology, both postnatally and at adulthood in different brain regions, that differently affect mood and cognition. The chronic blockade of adenosine A2A receptors (A2AR), which are core regulators of microglia morphology and physiology, ameliorated the cognitive deficits, but not the anxiety‐like behavior. Notably, A2AR blockade rectified both microglia morphology in the dHIP and the lack of mPFC‐dHIP synchronization, further heralding their role in cognitive function.

Microglia cytoarchitecture in the brain of adenosine A2A receptor knockout mice: Brain region and sex specificities

“…Differences in the cytoarchitecture of microglia between brain regions are in line with region‐specific functionalities already described for these cells (Grabert et al., ), reflecting a tight connection with the evolving neuronal network (Tremblay, Lowery, & Majewska, ; Wake, Moorhouse, Jinno, Kohsaka, & Nabekura, ). We recently described the same dichotomy between the PFC and the dHIP in a different rodent species, adult female rats (Caetano et al., ; Duarte et al., ), bolstering the appealing idea that the existence of sex‐specific microglia pools might be conserved among species in different brain regions. Interestingly, it has been already described that, in the early postnatal period, females have more round‐shaped phagocytic microglia than males in the dHIP (Nelson, Warden, & Lenz, ).…”

“…Besides these sex differences observed in physiological conditions, we described a sexspecific process of morphologic remodelling upon prenatal exposure to a stress mediator associated to chronic anxiety: in the PFC, microglia from male rats display an overall hypertrophy, while an atrophy was observed in females (Caetano et al, 2017). The morphologic adaptation to this prenatal stimulus seems to be differently regulated in different brain regions, considering that we observed the opposite in the dorsal hippocampus (dHIP; Duarte et al, 2018). The observation that both males and females exhibit anxious-like behaviour, regardless sex differences in microglia morphology in the PFC and in the dHIP, led us to explore the morphologic and functional consequences of changing microglia morphology, by using a selective adenosine A 2A receptors (A 2A R) antagonist, a modulator of microglia physiology and morphology (Caetano et al, 2017;George et al, 2015;Gomes et al, 2013;Gyoneva, Swanger, Zhang, Weinshenker, & Traynelis, 2016;Orr, Orr, Li, Gross, & Traynelis, 2009;Santiago et al, 2014).…”

“…First, the species used (rats vs. mice) eventually suggesting that the role of A 2A R in the regulation of microglia is not conserved among species. Another explanation could be the nature and time window of the manipulation: the genetic deletion in A 2A R KO is established during brain development (Chen et al, 1999;Huang et al, 2006;Yu et al, 2004), whereas the pharmacologic blockade was performed at adulthood (Caetano et al, 2017;Duarte et al, 2018). It is not mandatory that the consequences of a pharmacologic approach are the same as those caused by a genetic manipulation; F I G U R E 3 The genetic deletion of A 2A R induces a regional sex-specific structural remodelling of the morphological subpopulations of microglia in the dorsal hippocampus and in the prefrontal cortex | 1385 SimõeS-HenriqueS et al certainly, both strategies result in complementary data, which must be cautiously interpreted and correlated.…”

“…On the other hand, this treatment exacerbated microglia atrophy in the PFC and did not show any anxiolytic effect in females (Caetano et al., ). A 2A R blockade, although inefficient in ameliorating anxiety, was able to normalize cognitive deficits in females, in line with its ability to amend microglia morphology in the dHIP (Duarte et al., ). These contrasting dimorphic morphological alterations, paralleled by differential behavioural modulation, highlight the importance of these cells in neuropsychiatric disorders, warning for the need to consider sex when advancing therapeutic strategies.…”

“…Colonization is accompanied by a process of maturation from an amoeboid shape to a ramified phenotype, the typical morphology found in the adult healthy brain (Dalmau, Vela, González, Finsen, & Castellano, ). Microglia challenging during brain development has been linked to the aetiology of disorders with a developmental basis (van Berckel et al., ; Van den Eynde et al., ; Zhao et al., ), being implicated in psychiatric pathologies (Claypoole, Zimmerberg, & Williamson, ; Hellwig et al., ; Li, Ma, Kulesskaya, Võikar, & Tian, ) which are accompanied by changes in microglia density (Claypoole et al., ) and morphology (Caetano et al., ; Duarte et al., ). Microglia present sex‐specific profiles in the expression of chemokines and cytokines (Bollinger, Bergeon Burns, & Wellman, ; Schwarz et al., ) which correlate with morphological rearrangements (reviewed in (Clark & Malcangio, ) and retain a morphologic sex imprint across brain regions, namely in the hippocampus, parietal cortex, amygdala (Schwarz et al., ), preoptic area (Lenz, Nugent, Haliyur, & McCarthy, ) and prefrontal cortex (PFC; Caetano et al., ).…”