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(2A)R) control axon formation/outgrowth and synapse stabilization during development, we now examined the contribution of A(2A)R to MF sprouting. A(2A)R blockade significantly attenuated status epilepticus(SE)-induced MF sprouting in a rat pilocarpine model. This involves A(2A)R located in dentate granule cells since their knockdown selectively in dentate granule cells reduced MF sprouting, most likely through the ability of A(2A)R to induce the formation/outgrowth of abnormal secondary axons found in rat hippocampal neurons. These A(2A)R 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(2A)R contribute to epilepsy-related MF sprouting, most likely through the reactivation of the ability of A(2A)R to control axon formation/outgrowth observed during neurodevelopment. These results frame the CD73-A(2A)R axis as a regulator of circuit remodeling in the mature brain.