Caffeine is believed to be the world's most widely used psychoactive stimulant and if you've ever been stuck in a long queue at your local Starbucks, it would be difficult to argue. For many, daily caffeine intake, usually in the form of one or more cups of coffee, serves to increase alertness and mental acuity; however, the precise cellular and molecular mechanisms that mediate these effects are not clear.

Caffeine is an antagonist of the purinergic, G protein–coupled A1 adenosine receptor (A1R) and previous studies have suggested that inhibition of the A1Rs in the CA1 region of the hippocampus can induce an enhancement of long-term potentiation. However, it is the less well-characterized CA2 region that contains the highest concentrations of these adenosine-activated receptors and thus represents a potential target for caffeine. Similar to the adjacent CA1, the CA2 region receives specialized inputs from the CA3, which are known as Schaffer collaterals. Unlike those that project to the CA1, however, these inputs do not appear to exhibit activity-dependent potentiation, suggesting that, if caffeine does modulate synaptic plasticity, it would do so via a different mechanism. In a Brief Communication on page 24, Simons and colleagues show that physiological doses of caffeine can selectively modulate synaptic transmission in the CA2 region of the hippocampus via a mechanism that is independent of the traditional NMDA/Ca2+-mediated plasticity.

The authors found that if they fed juvenile rats with physiological doses of caffeine and, 1 h later, recorded from hippocampal tissue slices, there was a significant increase in the amplitude of excitatory postsynaptic currents in the CA2, but not in the CA1, region and that this effect did not result from a change in neuronal excitability. They found the same effect when caffeine was added directly to naive hippocampal slices, further supporting the specificity of this effect. This change in synaptic responsiveness persisted for at least 3 h.

In the CA1 region, induction of long-term potentiation is dependent on NMDA receptor activation and consequent Ca2+-dependent signaling. However, the authors found that the A1R-mediated CA2 potentiation was not perturbed by a calcium chelator, an NMDA receptor antagonist or inhibitors of calcium signaling. Instead, this synaptic plasticity was potently blocked by the addition of pharmacological inhibitors of either adenylyl cyclase or protein kinase A, which is consistent with the fact that the A1Rs are known to be coupled to the adenylyl cyclase–modulating Gi/o proteins. In addition, blockade of the MAPK signaling pathway also appeared to mitigate the stabilization of the A1R-dependent plasticity, hinting at a more complex signaling mechanism governing the consolidation of this synaptic plasticity.

Although it remains unclear whether the burst of mental clarity you receive from your morning coffee is a direct result of caffeine inhibiting adenosine receptors in the CA2 region of the hippocampus, this report provides a good starting point to unravel the mechanisms by which caffeine stimulates the brain.