Astrocytic A2A receptors silencing negatively impacts hippocampal synaptic plasticity and memory of adult mice

• Published in: Glia 2023-09, Vol.71 (9), p.2137-2153
• Main Authors: Madeira, Daniela, Lopes, Cátia R., Simões, Ana P., Canas, Paula M., Cunha, Rodrigo A., Agostinho, Paula
• Format: Article
• Language: English
• Subjects: Adenosine; Adenosine A2A receptors; Astrocytes; Glial fibrillary acidic protein; Hippocampal plasticity; Hippocampus; Long-term potentiation; memory; Morphology; Plasticity; Receptors; Spatial memory; Synapses; Synaptic plasticity
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.24384

Astrocytes are wired to bidirectionally communicate with neurons namely with synapses, thus shaping synaptic plasticity, which in the hippocampus is considered to underlie learning and memory. Adenosine A2A receptors (A2AR) are a potential candidate to modulate this bidirectional communication, since A2AR regulate synaptic plasticity and memory and also control key astrocytic functions. Nonetheless, little is known about the role of astrocytic A2AR in synaptic plasticity and hippocampal‐dependent memory. Here, we investigated the impact of genetic silencing astrocytic A2AR on hippocampal synaptic plasticity and memory of adult mice. The genetic A2AR silencing in astrocytes was accomplished by a bilateral injection into the CA1 hippocampal area of a viral construct (AAV5‐GFAP‐GFP‐Cre) that inactivate A2AR expression in astrocytes of male adult mice carrying “floxed” A2AR gene, as confirmed by A2AR binding assays. Astrocytic A2AR silencing alters astrocytic morphology, typified by an increment of astrocytic arbor complexity, and led to deficits in spatial reference memory and compromised hippocampal synaptic plasticity, typified by a reduction of LTP magnitude and a shift of synaptic long‐term depression (LTD) toward LTP. These data indicate that astrocytic A2AR control astrocytic morphology and influence hippocampal synaptic plasticity and memory of adult mice in a manner different from neuronal A2AR. Main Points Validation of an approach to silence astrocytic A2AR in the hippocampus of adult mice. Astrocytic A2AR modulate hippocampal synaptic plasticity, namely LTP and LTD, and hippocampaldependent memory. Astrocytic A2AR silencing increased the morphological complexity of astrocytes.