It is widely accepted that Hebbian forms of plasticity mediate selective modifications in synaptic strength underlying information encoding in response to experience and circuit formation or refinement throughout development. Several complementary forms of homeostatic plasticity coordinate to keep Hebbian plasticity in check, frequently through the actions of conserved regulatory molecules. Recent evidence suggests that this may be the case for adenosine, which is ubiquitous in the brain and is released by both neurons and glial cells via constitutive and activity-dependent mechanisms. Through A1 and A2A receptor activation, adenosine modulates neuronal homeostasis and tunes the ability of synapses to undergo and/or sustain plasticity. Here, we review how adenosine equilibrates neuronal activity and sets the stage for synaptic plasticity.
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