Astrocytic adenosine receptor A(2A) and G(s)-coupled signaling regulate memory

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/Arg3.1, an immediate-early gene required for long-term memory. Chemogenetic activation of astrocytic G(s)-coupled signaling reduced long-term memory in mice without affecting learning. Similar to 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.