Caffeine-Mediated Presynaptic Long-Term Potentiation in Hippocampal CA1 Pyramidal Neurons

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Abstract
We report a new form of long-term potentiation (LTP) in Schaffer collateral (SC)-CA1 pyramidal neuron synapses that originates presynaptically and does not require N-methyl-d-aspartate (NMDA) receptor activation nor increases in postsynaptic-free Ca2+. Using rat hippocampal slices, application of a brief “pulse” of caffeine in the bath evoked a nondecremental LTP (CAFLTP) of SC excitatory postsynaptic currents. An increased probability of transmitter release paralleled theCAFLTP, suggesting that it originated presynaptically. The P1adenosine receptor antagonist 8-cyclopentyltheophylline and the P2purinoreceptor antagonists suramin and piridoxal-5′-phosphate-azophenyl 2′,4′-disulphonate blocked theCAFLTP. Inhibition of Ca2+release from caffeine/ryanodine stores by bath-applied ryanodine inhibited theCAFLTP, but ryanodine in the pipette solution was ineffective, suggesting a presynaptic effect of ryanodine. Previous induction of the “classical” LTP did not prevent theCAFLTP, suggesting that the LTP and theCAFLTP have different underlying cellular mechanisms. TheCAFLTP is insensitive to the block of NMDA receptors by 2-amino-5-phosphonopentanoic acid and to Ca2+chelation with intracellular 1,2-bis (2-aminophenoxy) ethane- N,N,N′ ,N′-tetraacetic acid, indicating that neither postsynaptic NMDA receptors nor increases in cytosolic-free Ca2+participate in theCAFLTP. We conclude that theCAFLTP requires the interaction of caffeine with presynaptic P1, P2purinoreceptors, and ryanodine receptors and is caused by an increased probability of glutamate release at SC terminals.