title: Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory.
abstract: Astrocytes express a variety of G protein-coupled receptors and might influence cognitive functions, such as learning and memory. However, the roles of astrocytic Gs-coupled receptors in cognitive function are not known. We found that humans with Alzheimer's disease (AD) had increased levels of the Gs-coupled adenosine receptor A2A 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 Gs-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 A2A receptors. Conditional genetic removal of these receptors enhanced memory in aging hAPP mice. Together, these findings establish a regulatory role for astrocytic Gs-coupled receptors in memory and suggest that AD-linked increases in astrocytic A2A receptor levels contribute to memory loss.
authors.affiliation: 1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, California, USA.
authors.forename: Anna G
authors.initials: AG
authors.lastname: Orr
authors.affiliation: 1] Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA. [2] Division of Endocrinology and Metabolism, Department of Medicine, and the Institute for Human Genetics, University of California, San Francisco, California, USA.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Hsiao
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, USA.
authors.forename: Max M
authors.initials: MM
authors.lastname: Wang
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, USA.
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Ho
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, USA.
authors.forename: Weikun
authors.initials: W
authors.lastname: Guo
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Kang
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, USA.
authors.forename: Gui-Qiu
authors.initials: GQ
authors.lastname: Yu
authors.affiliation: 1] Department of Neuroscience, University of California, San Diego, La Jolla, California, USA. [2] Department of Pathology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, USA.
authors.forename: Nino
authors.initials: N
authors.lastname: Devidze
authors.affiliation: 1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, California, USA.
authors.forename: Dena B
authors.initials: DB
authors.lastname: Dubal
authors.affiliation: 1] Department of Neuroscience, University of California, San Diego, La Jolla, California, USA. [2] Department of Pathology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: 1] Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA. [2] Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Conklin
authors.affiliation: 1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, California, USA.
authors.forename: Lennart
authors.initials: L
authors.lastname: Mucke
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D018782:Maze Learning / Q000502:physiology; D057567:Memory, Long-Term / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D044422:Receptors, Serotonin, 5-HT4 / Q000235:genetics / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D003598:Cytoskeletal Proteins; D005904:Glial Fibrillary Acidic Protein; D007211:Indoles; D009419:Nerve Tissue Proteins; D043705:Receptor, Adenosine A2A; D012702:Serotonin Antagonists; D013449:Sulfonamides; C092069:activity regulated cytoskeletal-associated protein; D044422:Receptors, Serotonin, 5-HT4; C082871:GR 113808