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.

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