Adenosine A_2A receptors control synaptic remodeling in the adult brain

The molecular mechanisms underlying circuit re-wiring in the mature brain remains ill-defined. An eloquent example of adult circuit remodelling is the hippocampal mossy fiber (MF) sprouting found in diseases such as temporal lobe epilepsy. The molecular determinants underlying this retrograde re-wiring remain unclear. This may involve signaling system(s) controlling axon specification/growth during neurodevelopment reactivated during epileptogenesis. Since adenosine A_2A receptors (A_2AR) control axon formation/outgrowth and synapse stabilization during development, we now examined the contribution of A_2AR to MF sprouting. A_2AR blockade significantly attenuated status epilepticus(SE)-induced MF sprouting in a rat pilocarpine model. This involves A_2AR located in dentate granule cells since their knockdown selectively in dentate granule cells reduced MF sprouting, most likely through the ability of A_2AR to induce the formation/outgrowth of abnormal secondary axons found in rat hippocampal neurons. These A_2AR should be activated by extracellular ATP-derived adenosine since a similar prevention/attenuation of SE-induced hippocampal MF sprouting was observed in CD73 knockout mice. These findings demonstrate that A_2AR contribute to epilepsy-related MF sprouting, most likely through the reactivation of the ability of A_2AR to control axon formation/outgrowth observed during neurodevelopment. These results frame the CD73-A_2AR axis as a regulator of circuit remodeling in the mature brain.