The Effect of Caffeine on Various Forms of Synaptic Plasticity in the CA1 Region of Mouse Hippocampal Slices

Caffeine is the most widely used psychoactive compound. In the brain, caffeine acts as a competitive, non-selective adenosine receptor antagonist of A1 and A2A, both known to modulate long-term potentiation (LTP), the cellular basis of learning and memory. But the effects of caffeine on synaptic function and plasticity cannot be reduced to a single inhibitory or facilitatory action. In the CA1 area of the hippocampus, low-micromolar caffeine has been reported to attenuate LTP, yet it remains unclear whether this action extends equally to other plasticity-related responses, including EPSP–spike coupling and paired-pulse responses. Here, we studied the effect of 30 μM caffeine on the field excitatory postsynaptic potentials (fEPSPs) and LTP evoked by Schaffer collateral stimulation in the CA1 region in mouse hippocampal slices. We compared theta-burst-induced long-term fEPSP potentiation, EPSP–spike (E-S) potentiation, input–output relationships, and paired-pulse responses after short (three burst-TBS3) and long (ten burst-TBS10) theta-burst stimulation. Caffeine attenuated long-term fEPSP potentiation induced by the longer theta-burst protocol and reduced the accompanying increase in population spike amplitude. In contrast, E-S potentiation induced by the shorter theta-burst protocol was preserved under caffeine exposure. Input–output analysis further showed that caffeine prevented the increase in population spike amplitude accompanying the development of long-term fEPSP potentiation, but did not prevent the population spike response changes associated with E-S potentiation. Caffeine also reduced paired-pulse deviations from 100%, most clearly for population spike amplitude, and this effect persisted after both the theta-burst protocols. Thus, 30 μM caffeine did not simply suppress CA1 plasticity-related responses, but distinguished TBS10-induced synaptic fEPSP potentiation from TBS3-induced EPSP–spike potentiation. These findings identify EPSP–spike coupling as a caffeine-preserved CA1 plasticity-related response and provide a basis for future receptor-selective and behavioral testing.