Retrograde adenosine/A2A receptor signaling facilitates excitatory synaptic transmission and seizures
Kaoutsar Nasrallah, Coralie Berthoux, Yuki Hashimotodani, Andrés E. Chávez, Michelle C. Gulfo, Rafael Luján, Pablo E. Castillo
Abstract
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 2A R) 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 2A Rs were necessary and sufficient for LTP. Lastly, seizure induction released adenosine in a TrkB-dependent manner, while removing A 2A Rs or TrkB from the dentate gyrus had anti-convulsant effects. By mediating presynaptic LTP, adenosine/A 2A R retrograde signaling may modulate dentate gyrus-dependent learning and promote epileptic activity.