Striatopallidal adenosine A2A receptor modulation of goal-directed behavior: Homeostatic control with cognitive flexibility

Astrocytic A2A receptors silencing negatively impacts hippocampal synaptic plasticity and memory of adult mice

“…This allows concluding that astrocytic A 2A R seem to cooperate with synaptic A 2A R to sustain LTP (see Costenla et al, 2011;Rebola et al, 2008) whereas astrocytic A 2A R stabilize hippocampal LTD in contrast to synaptic A 2A R that destabilize hippocampal LTD (Temido-Ferreira et al, 2020). The existence of different A 2A R populations located in different cell types with opposite effects on brain function has been previously been noted (Li et al, 2018;Shen et al, 2008Shen et al, , 2013Wei et al, 2014) and is probably related with the homeostatic role of the A 2A R to assist encoding the parallel preservation and flexibility of different behavioral outputs based on a proposed spatiotemporally controlled activation of A 2A R in different compartments (reviewed in Chen et al, 2023). Remarkably, one behavioral consequence of the selective silencing of A 2A R in astrocytes is a decreased memory performance, which contrasts with the preservation of memory function observed in mice with a selective deletion of A 2A R in forebrain neurons (Gonçalves et al, 2019;Kaster et al, 2015) or in rodents treated with A 2A R antagonists (Canas et al, 2009;Cognato et al, 2010;Cunha et al, 2008;Faivre et al, 2018;Moreira-de-Sá et al, 2020;Orr et al, 2018;Prediger et al, 2005;Silva et al, 2018; Viana da .…”

“…The clarification of the role of astrocytic A 2A R in the control of hippocampal synaptic plasticity and spatial memory is also relevant to understand the interest of targeting A 2A R to manage brain diseases involving memory dysfunction (reviewed in Cunha, 2016). In fact, A 2A R antagonists (or genetic deletion) afford a robust neuroprotection in animal models of epilepsy (reviewed in Tescarollo et al, 2020), ischemia (Chen et al, 1999), stress‐induced depression (Kaster et al, 2015), Alzheimer's (Canas et al, 2009; Carvalho et al, 2019; Viana da Silva et al, 2016) or Parkinson's disease (reviewed in Chen et al, 2023). Conversely, the pharmacological (Pagnussat et al, 2015), genetic (Temido‐Ferreira et al, 2020) or optogenetic (Li et al, 2015) overactivation of A 2A R is sufficient to trigger brain dysfunction, namely memory impairment.…”

Adenosine A2A Receptor Up-Regulation Pre-Dates Deficits of Synaptic Plasticity and of Memory in Mice Exposed to Aβ1–42 to Model Early Alzheimer’s Disease

“…These will probably involve the engagement of different heteromers containing A 2A R (reviewed in [ 94 ]) and the coupling of A 2A R to different transducing mechanisms, which may change with the evolution of brain diseases and the upregulation of A 2A R (reviewed in [ 14 ]). Thus, understanding the spatiotemporal dynamics of A 2A R signaling in different compartments—which often have opposite effects on synaptic and behavioral outputs (see [ 95 , 96 , 97 , 98 ])—will be critical to understand this apparently paradoxical ability of A 2A R blockade to prevent aberrant hyperexcitability and normalize synaptic plasticity both when it is increased as well as when it is decreased.…”

Sensorineural hearing loss and cognitive impairment: three hypotheses

“…In contrast to the neuroprotective effect of A1R in the ear, inhibition of adenosine A2A receptor (A2AR) increases the resistance of the cochlea to acoustic damage ( Vlajkovic et al, 2017 ; Shin et al, 2021 ; Oliveros et al, 2022 ). Within the cranium, activation of A2AR promotes neuroinflammation, reducing synaptic plasticity ( Merighi et al, 2022 ; Chen et al, 2023 ). However, adenosine A2B receptor was shown to have the opposite effect of A1R ( Qiang et al, 2021 ).…”