Adjusting the brakes to adjust neuronal activity: Adenosinergic modulation of GABAergic transmission

About 50 years elapsed from the publication of the first full paper on the neuromodulatory action of adenosine at a 'simple' synapse model, the neuromuscular junction (Ginsborg and Hirst, 1972). In that study adenosine was used as a tool to increase cyclic AMP and for the great surprise, it decreased rather than increased neurotransmitter release, and for a further surprise, its action was prevented by theophylline, at the time only known as inhibitor of phosphodiesterases. These intriguing observations opened the curiosity for immediate studies relating the action of adenine nucleotides, known to be released together with neurotransmitters, to that of adenosine (Ribeiro and Walker, 1973, 1975). Our understanding on the ways adenosine uses to modulate synapses, circuits, and brain activity, vastly expanded since then. However, except for A2A receptors, whose actions upon GABAergic neurons of the striatum are well known, most of the attention given to the neuromodulatory action of adenosine has been focusing upon excitatory synapses. Evidence is growing that GABAergic transmission is also a target for adenosinergic neuromodulation through A1 and A2A receptors. Some o these actions have specific time windows during brain development, and others are selective for specific GABAergic neurons. Both tonic and phasic GABAergic transmission can be affected, and either neurons or astrocytes can be targeted. In some cases, those effects result from a concerted action with other neuromodulators. Implications of these actions in the control of neuronal function/dysfunction will be the focus of this review.This article is part of the Special Issue on Purinergic Signaling: 50 years.

Automated summary

It has been about 50 years since the first full paper on the neuromodulatory action of adenosine was published. Adenosine was initially used to increase cyclic AMP, but surprisingly, it decreased neurotransmitter release. Further studies revealed the relationship between adenosine and adenine nucleotides. Our understanding of adenosine's modulation of synapses, circuits, and brain activity has greatly expanded since then. While most attention has been on excitatory synapses, evidence suggests that adenosine also modulates GABAergic transmission through A1 and A2A receptors, with specific effects on different GABAergic neurons and time windows during brain development. The implications of these actions in neuronal function and dysfunction will be the focus of this review.