In vertebrate hippocampal neurons, application of forskolin (an adenylyl cyclase activator) and rolipram (a phosphodiesterase inhibitor) is an effective technique for inducing chemical LTP (cLTP) that is NMDA receptor (NMDAR)-dependent (Otmakhov et al. 2004). However, it is not known whether forskolin induces a similar potentiation in invertebrate synapses. Therefore, we examined whether forskolin plus rolipram treatment could induce potentiation at a known glutamatergic synapse in the leech (Hirudo sp.), specifically between the pressure (P) mechanosensory and anterior pagoda (AP) neurons. Perfusion of isolated ganglia with forskolin (50 µM) in conjunction with rolipram (0.1 µM) in Mg²⁺-free saline significantly potentiated the P-to-AP EPSP. Application of APV (100 µM), a competitive NMDAR antagonist, blocked the potentiation, indicating P-to-AP potentiation is NMDAR-dependent. Potentiation was blocked by injection of BAPTA (1mM) into the postsynaptic cell, but not by BAPTA injection into the presynaptic neuron, indicating a requirement for postsynaptic elevation of intracellular Ca²⁺. Application of db-cAMP mimicked the potentiating effects of forskolin, and Rp-cAMP, an inhibitor of PKA, blocked forskolin-induced potentiation. Potentiation was also blocked by autocamtide-2-related inhibitory peptide, indicating a requirement for activation of Ca²⁺/calmodulin-dependent kinase II (CaMKII). Finally, potentiation was blocked by botulinum toxin, suggesting that trafficking of glutamate receptors also plays a role in this form of synaptic plasticity. These experiments demonstrate that techniques used to induce cLTP in vertebrate synapses also induces NMDAR-dependent potentiation in the leech CNS and that many of the cellular processes that mediate LTP are conserved between vertebrate and invertebrate phyla.