Upregulation of adenosine A_2A receptor in 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 A₁ (A₁R) and A_2A (A_2AR) receptors. Interestingly, A_2AR 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_2AR in astrocytes remain poorly understood. In the present study, we induced the upregulation of A_2AR in hippocampal astrocytes using dedicated AAVs and comprehensively evaluated the functional consequences in 4 months-old C57Bl6/J mice. Our results show that A_2AR upregulation primarily promotes alterations of astrocyte reactivity, morphology and transcriptome, with a link to aging-like phenotype as well as secondary impairments of neuronal excitability and microglial phenotype. These changes driven by a restricted A_2AR upregulation in hippocampal astrocytes were sufficient to induce impairments of short-term spatial memory and spatial learning. This study highlights the impact of astrocytic A_2AR 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.