Influence of Adenosine on Synaptic Excitability

Abstract

Adenosine affects synaptic excitability primarily through a delicate balance between Gi/o-coupled adenosine A1 receptors (A1Rs), which in general inhibit transmission, and Gs-coupled adenosine A2A receptors (A2ARs), which increase synaptic excitability and contribute to synaptic plasticity. Crosstalk between A2AR signaling and the TrkB receptor allows for modification of brain derived neurotrophic factor-mediated plasticity. Adenosine homeostasis is largely under the control of astrocytes and metabolic clearance through adenosine kinase. The tripartite synapse thereby plays an important role in fine-tuning adenosinergic signaling. Those multifaceted actions of adenosine are of paramount importance for the pathogenesis and pathophysiology of epilepsy. Progressive disruption of adenosine homeostasis is a major driving force in epileptogenesis, where adenosine receptor-dependent and -independent mechanisms play a role. Consequently, therapeutic adenosine augmentation is not only a therapeutic strategy for the treatment of seizures, but also for the prevention of epilepsy.