Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory

The authors show that astrocytes produce high levels of the adenosine receptor A2A in Alzheimer brains. Reducing the levels of astrocytic A2A boosted memory in young and aging mice and mouse models of Alzheimer disease, whereas activating a related molecular pathway impaired memory. Thus, astrocytes regulate memory and abnormal receptor activity in these cells may contribute to memory disorders. Astrocytes express a variety of G protein–coupled receptors and might influence cognitive functions, such as learning and memory. However, the roles of astrocytic G s -coupled receptors in cognitive function are not known. We found that humans with Alzheimer's disease (AD) had increased levels of the G s -coupled adenosine receptor A 2A in astrocytes. Conditional genetic removal of these receptors enhanced long-term memory in young and aging mice and increased the levels of Arc (also known as Arg3.1 ), an immediate-early gene that is required for long-term memory. Chemogenetic activation of astrocytic G s -coupled signaling reduced long-term memory in mice without affecting learning. Like humans with AD, aging mice expressing human amyloid precursor protein (hAPP) showed increased levels of astrocytic A 2A receptors. Conditional genetic removal of these receptors enhanced memory in aging hAPP mice. Together, these findings establish a regulatory role for astrocytic G s -coupled receptors in memory and suggest that AD-linked increases in astrocytic A 2A receptor levels contribute to memory loss.