Genetic deletion of adenosine A2A receptors attenuates memory deterioration and alterations of synaptic plasticity and metabolic controllers in the hippocampus and prefrontal cortex of aged mice

The incidence of brain diseases increases with aging, but the biological basis of brain aging is still poorly explored. Synaptic dysfunction occurs at the onset of brain diseases and synaptic neuromodulation systems, such as adenosine A2A receptors (A2AR), are necessary and sufficient to trigger brain dysfunction. Since A2AR are upregulated upon aging, we compared wild-type and A2AR global knockout mice to test if brain aging involves synaptic senescence linked to A2AR overfunction, leading to synaptic and cognitive deterioration. Aging impacted different behavioral outputs, namely spatial learning and memory, coupled to aberrant synaptic plasticity in the hippocampus and prefrontal cortex. Moreover, aging led to an imbalance between excitation and inhibition markers and dysregulated key metabolic coordinators, including sirtuin-1, sirtuin-3, AMPK and p38MAPK. These cognitive impairments and synaptic and metabolic signaling alterations were not observed in aged mice with A2AR genetic elimination. These findings suggest that A2AR overfunction can be a key driver of age-associated memory deterioration and A2AR blockade might promote healthy brain aging.