Retrograde signaling at the synapse is a fundamental way by which neurons communicate and neuronal circuit function is fine-tuned upon activity. While long-term changes in neurotransmitter release commonly rely on retrograde signaling, the mechanisms remain poorly understood. Here, we identified adenosine/A2A receptor (A2AR) as a retrograde signaling pathway underlying presynaptic long-term potentiation (LTP) at a hippocampal excitatory circuit critically involved in memory and epilepsy. Transient burst activity of a single dentate granule cell induced LTP of mossy cell synaptic inputs, a BDNF/TrkB-dependent form of plasticity that facilitates seizures. Postsynaptic TrkB activation released adenosine from granule cells, uncovering a non-conventional BDNF/TrkB signaling mechanism. Moreover, presynaptic A2ARs were necessary and sufficient for LTP. Lastly, seizure induction released adenosine in a TrkB-dependent manner, while removing A2ARs or TrkB from the dentate gyrus had anti-convulsant effects. By mediating presynaptic LTP, adenosine/A2AR retrograde signaling may modulate dentate gyrus-dependent learning and promote epileptic activity. Display omitted •Postsynaptic firing induces presynaptic LTP at mossy cell to granule cell synapses•Postsynaptic TrkB activation induces adenosine release from granule cells•Presynaptic adenosine A2A receptors are necessary and sufficient to induce LTP•Adenosine/A2AR signaling within the dentate gyrus is pro-convulsant Nasrallah et al. report a retrograde signaling pathway at hippocampal synapses that involves postsynaptic TrkB-dependent release of adenosine and the activation of presynaptic A2A receptors. This pathway mediates presynaptic long-term potentiation at a key hippocampal excitatory synapse and can also promote epileptic seizures.