Adenosine A_2A receptor involves in neuroinflammation-mediated cognitive decline through activating microglia under...

Hypobaric hypoxia (HH) at high altitudes leads to a wide range of cognitive impairments which can handicap human normal activities and performances. However, the underlying mechanism is still unclear. Adenosine A_2A receptors (A_2ARs) of the brain are pivotal to synaptic plasticity and cognition. Besides, insult-induced up-regulation of A_2AR regulates neuroinflammation and therefore induces brain damages in various neuropathological processes. The present study was designed to determine whether A_2AR-mediate neuroinflammation involves in cognitive impairments under acute HH. A_2AR knock-out and wild-type male mice were exposed to a simulated altitude of 8000 m for 7 consecutive days in a hypobaric chamber and simultaneously received behavioral tests including Morris water maze test and open filed test. A_2AR expression, the activation of microglia and the production of TNF-α were evaluated in the hippocampus by immunohistochemistry and ELISA, respectively. Behavioral tests showed that acute HH exposure caused the dysfunction of spatial memory and mood, while genetic inactivation of A_2AR attenuated the impairment of spatial memory but not that of mood. Double-labeled immunofluorescence showed that A_2ARs were mainly expressed on microglia and up-regulated in the hippocampus of acute HH model mice. Acute HH also induced the accumulation of microglia and increased production of TNF-α in the hippocampus, which could be markedly inhibited by A_2AR inactivation. These findings indicate that microglia-mediated neuroinflammation triggered by A_2AR activation involves in acute HH-induced spatial memory impairment and that A_2AR could be a new target for the pharmacotherapy of cognitive dysfunction at high altitudes.