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

Abstract

AbstractA long-term change in neurotransmitter release is a widely expressed mechanism controlling neural circuits in the mammalian brain. This presynaptic plasticity is commonly mediated by retrograde signaling whereby a messenger released from the postsynaptic neuron upon activity modifies neurotransmitter release in a long-term manner by targeting a presynaptic receptor. In the dentate gyrus (DG), the main input area of the hippocampus, granule cells (GCs) and mossy cells (MCs) form a recurrent excitatory circuit that is critically involved in DG function and epilepsy. Here, we identified adenosine/A2A receptor (A2AR) as a novel retrograde signaling system that mediates presynaptic long-term potentiation (LTP) at MC-GC synapses. Using an adenosine sensor, we found that neuronal activity triggered phasic, postsynaptic TrkB-dependent release of adenosine. Additionally, epileptic seizures released adenosine in vivo, while removing A2ARs from DG decreased seizure susceptibility. Thus, adenosine/A2AR retrograde signaling mediates presynaptic LTP that may contribute to DG-dependent learning and promote epilepsy.