Retrograde adenosine/A2A receptor signaling facilitates excitatory synaptic transmission and seizures

• Published in: Cell reports (Cambridge) 2024-07, Vol.43 (7), p.114382-114382, Article 114382
• Main Authors: Nasrallah, Kaoutsar, Berthoux, Coralie, Hashimotodani, Yuki, Chávez, Andrés E., Gulfo, Michelle C., Luján, Rafael, Castillo, Pablo E.
• Format: Article
• Language: English
• Subjects: BDNF; CP: Neuroscience; dentate gyrus; epilepsy; hippocampus; LTP; mossy cell; PKA; presynaptic; retrograde signaling; TrkB
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114382

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.