AbstractNeurodegeneration is a process transversal to neuropsychiatric diseases and the understanding of its mechanisms should allow devising strategies to prevent this irreversible step in brain diseases. Neurodegeneration caused by seizures is a critical step in the aggravation of temporal lobe epilepsy, but its mechanisms remain undetermined. Convulsions trigger an elevation of extracellular adenosine and upregulate adenosine A_2Areceptors (A_2AR), which have been associated with the control of neurodegenerative diseases. Using the rat and mouse kainate model of temporal lobe epilepsy, we now tested whether A_2AR control convulsions-induced hippocampal neurodegeneration. The pharmacological or genetic blockade of A_2AR did not affect kainate-induced convulsions but dampened the subsequent neurotoxicity. This neurotoxicity began with a rapid A_2AR upregulation within glutamatergic synapses (within 2 h), through local translation of synaptic A_2AR mRNA. This bolstered A_2AR-mediated facilitation of glutamate release and of long-term potentiation (LTP) in CA1 synapses (4 h), triggered a subsequent synaptotoxicity, heralded by decreased synaptic plasticity and loss of synaptic markers coupled to calpain activation (12 h), that predated overt neuronal loss (24 h). All modifications were prevented by the deletion of A_2AR selectively in forebrain neurons. This shows that synaptic A_2AR critically control synaptic excitotoxicity, which underlies the development of convulsions-induced neurodegeneration.