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

Abstract 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 A 2A receptors (A 2A R), are necessary and sufficient to trigger brain dysfunction. Since A 2A R are upregulated upon aging, we compared wild-type and A 2A R global knockout mice to test if brain aging involves synaptic senescence linked to A 2A R 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 A 2A R genetic elimination. These findings suggest that A 2A R overfunction can be a key driver of age-associated memory deterioration and A 2A R blockade might promote healthy brain aging. Graphical abstract Aging affected memory and synaptic plasticity, disrupted the balance between excitation and inhibition markers and deregulated key metabolic regulators, namely SIRT1, SIRT3, AMPK and p38MAPK, in the hippocampus and prefrontal cortex of aged mice. A 2A R elimination prevented memory deterioration and most synaptic and metabolic-related alterations in both cortical regions were no longer present. Thus, A 2A R upregulation might be a driver of synaptic senescence-like metabolic and A 2A R blockade may help prevent synaptic dysfunction and, consequently, promote healthy aging.