Retrograde adenosine/A2A receptor signaling facilitates excitatory synaptic transmission and 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/A_2A receptor (A_2AR) 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 A_2ARs were necessary and sufficient for LTP. Lastly, seizure induction released adenosine in a TrkB-dependent manner, while removing A_2ARs or TrkB from the dentate gyrus had anti-convulsant effects. By mediating presynaptic LTP, adenosine/A_2AR retrograde signaling may modulate dentate gyrus-dependent learning and promote epileptic activity.