Retrograde adenosine/A2A receptor signaling mediates presynaptic hippocampal LTP and facilitates epileptic seizures

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 novel 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. HighlightsO_LIPostsynaptic firing induces presynaptic LTP at mossy cell to granule cell synapses C_LIO_LIPostsynaptic TrkB activation induces adenosine release from granule cells C_LIO_LIPresynaptic adenosine A2A receptors are necessary and sufficient to induce LTP C_LIO_LIAdenosine/A2AR signaling within the dentate gyrus is pro-convulsant C_LI In BriefNasrallah et al. report a novel 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.