Upregulation of adenosine A2A receptor by astrocytes is sufficient to trigger hippocampal multicellular dysfunctions and memory deficits.

Adenosine is an ubiquitous neuromodulator that ensures cerebral homeostasis. It exerts numerous functions through the activation of G-protein-coupled adenosine receptors (ARs), in particular A ₁ (A ₁ R) and A _2A (A _2A R) receptors. Interestingly, A _2A R levels are upregulated in cortical and hippocampal regions in several pathological conditions such as Alzheimer’s disease, tauopathies or epilepsia. Such abnormal upregulations have been particularly reported in astrocytes, glial cells that play a key role in regulating synaptic plasticity. However, the overall impact and the underlying mechanisms associated with increased A _2A R in astrocytes remain poorly understood. In the present study, we induced the upregulation of A _2A R in hippocampal astrocytes using dedicated AAVs and comprehensively evaluated the functional consequences in 4 months-old C57Bl6/J mice. Our results show that A _2A R upregulation promotes cell-autonomous alterations of astrocyte reactivity, morphology and transcriptome, with a link to aging-like phenotype as well as non-cell autonomous impairments of neuronal excitability and microglial phenotype. These changes driven by a restricted A _2A R upregulation in hippocampal astrocytes were sufficient to induce impairments of short-term spatial memory (Y-Maze task) and spatial learning (Barnes Maze task). This study highlights the impact of astrocytic A _2A R upregulation, as seen in various neurological conditions, on the development of a detrimental multicellular response associated with memory alterations and provides an additional proof-of-concept for the value of targeting this receptor in different neurodegenerative conditions.