Abstract The α-Ca 2+/calmodulin kinase II (αCaMKlI) is required for long-term potentiation in the CA1 region of the hippocampus. Here, we report that this kinase also has a crucial role in presynaptic plasticity. Paired-pulse facilitation is blunted in the CAI region of mice heterozygous for a targeted mutation of αCaMKlI, confirming that this kinase can promote neurotransmitter release. Unexpectedly, field and whole-cell recordings of post-tetanic potentiation show that the synaptic responses of mutants are larger than those of controls, indicating that αCaMKII can also inhibit transmitter release immediately after tetanic stimulation. Thus, αCaMKII has the capacity either to potentiate or to depress excitatory synaptic transmission depending on the pattern of presynaptic activation.