Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory

Anna G Orr; Edward C Hsiao; Max M Wang; Kaitlyn Ho; Daniel H Kim; Xin Wang; Weikun Guo; Jing Kang; Gui-Qiu Yu; Anthony Adame; Nino Devidze; Dena B Dubal; Eliezer Masliah; Bruce R Conklin; Lennart Mucke

doi:10.1038/nn.3930

Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory

Nat Neurosci. 2015 Mar;18(3):423-34. doi: 10.1038/nn.3930. Epub 2015 Jan 26.

Authors

Affiliations

¹ 1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, California, USA.
² 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.
³ Gladstone Institute of Neurological Disease, San Francisco, California, USA.
⁴ 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.
⁵ 1] Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA. [2] Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA.

PMID: 25622143
PMCID: PMC4340760
DOI: 10.1038/nn.3930

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / pathology
Animals
Animals, Newborn
Astrocytes / metabolism*
Cytoskeletal Proteins / genetics
Cytoskeletal Proteins / metabolism
Exploratory Behavior / drug effects
Exploratory Behavior / physiology
Gene Expression Regulation / physiology*
Glial Fibrillary Acidic Protein / genetics
Glial Fibrillary Acidic Protein / metabolism
Humans
Indoles / pharmacology
Maze Learning / physiology
Memory, Long-Term / physiology*
Mice
Mice, Inbred C57BL
Mice, Transgenic
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism
Receptor, Adenosine A2A / genetics
Receptor, Adenosine A2A / metabolism*
Receptors, Serotonin, 5-HT4 / genetics
Receptors, Serotonin, 5-HT4 / metabolism*
Recognition, Psychology / drug effects
Recognition, Psychology / physiology
Serotonin Antagonists / pharmacology
Signal Transduction / physiology*
Sulfonamides / pharmacology

Substances

Cytoskeletal Proteins
Glial Fibrillary Acidic Protein
Indoles
Nerve Tissue Proteins
Receptor, Adenosine A2A
Serotonin Antagonists
Sulfonamides
activity regulated cytoskeletal-associated protein
Receptors, Serotonin, 5-HT4
GR 113808

Abstract

Publication types

MeSH terms

Substances

Grants and funding