Use of knockout mice to explore CNS effects of adenosine

The initial exploration using pharmacological tools of the role of adenosine receptors in the brain, concluded that adenosine released as such acted on A₁R to inhibit excitability and glutamate release from principal neurons throughout the brain and that adenosine A_2A receptors (A_2AR) were striatal-'specific' receptors controlling dopamine D₂R. This indicted A₁R as potential controllers of neurodegeneration and A_2AR of psychiatric conditions. Global knockout of these two receptors questioned the key role of A₁R and instead identified extra-striatal A_2AR as robust controllers of neurodegeneration. Furthermore, transgenic lines with altered metabolic sources of adenosine revealed a coupling of ATP-derived adenosine to activate A_2AR and a role of A₁R as a hurdle to initiate neurodegeneration. Additionally, cell-selective knockout of A_2AR unveiled the different roles of A_2AR in different cell types (neurons/astrocytes) in different portions of the striatal circuits (dorsal versus lateral) and in different brain areas (hippocampus/striatum). Finally, a new transgenic mouse line with deletion of all adenosine receptors seems to indicate a major allostatic rather than homeostatic role of adenosine and may allow isolating P2R-mediated responses to unravel their role in the brain, a goal close to heart of Geoffrey Burnstock, to whom we affectionately dedicate this review.