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Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory
Anna G Orr1, Edward C Hsiao2, Max M Wang3
11] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, California, USA.
Nature Neuroscience
|January 27, 2015
Summary
Astrocytes
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Astrocytes, a type of glial cell, express G protein-coupled receptors (GPCRs) that may influence cognitive functions like memory.
- The specific roles of astrocytic Gs-coupled receptors in cognitive processes remain largely unexplored.
- Dysregulation of astrocytic signaling is implicated in neurological disorders.
Purpose of the Study:
- To investigate the role of astrocytic Gs-coupled receptors in learning and memory.
- To determine the impact of adenosine receptor A2A (A2AR) levels in astrocytes on cognitive function.
- To explore the potential contribution of astrocytic A2ARs to Alzheimer's disease (AD) pathology.
Main Methods:
- Utilized conditional genetic manipulation to remove Gs-coupled receptors specifically in astrocytes.
- Employed chemogenetics to activate astrocytic Gs-coupled signaling.
- Measured long-term memory performance and levels of the immediate-early gene Arc (Arg3.1) in mice.
- Examined astrocytic A2A receptor levels in human AD brains and in mouse models of AD (hAPP mice).
Main Results:
- Increased astrocytic adenosine receptor A2A levels were observed in humans with Alzheimer's disease.
- Genetic removal of astrocytic Gs-coupled receptors enhanced long-term memory in young and aging mice.
- This enhancement correlated with increased levels of the memory-associated gene Arc (Arg3.1).
- Chemogenetic activation of astrocytic Gs-coupled signaling impaired long-term memory without affecting learning.
- Aging mice expressing human amyloid precursor protein (hAPP) exhibited elevated astrocytic A2A receptor levels, similar to human AD patients.
- Removing these receptors in aging hAPP mice improved memory function.
Conclusions:
- Astrocytic Gs-coupled receptors, particularly A2A receptors, play a regulatory role in long-term memory.
- Elevated astrocytic A2A receptor levels are associated with memory deficits in Alzheimer's disease models.
- Targeting astrocytic Gs-coupled signaling represents a potential therapeutic strategy for memory loss in AD.
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