RT Journal Article SR Electronic T1 Neuronal Adenosine A2A Receptors Are Critical Mediators of Neurodegeneration Triggered by Convulsions JF eneuro JO eNeuro FD Society for Neuroscience SP ENEURO.0385-18.2018 DO 10.1523/ENEURO.0385-18.2018 VO 5 IS 6 A1 Paula M. Canas A1 Lisiane O. Porciúncula A1 Ana Patrícia Simões A1 Elisabete Augusto A1 Henrique B. Silva A1 Nuno J. Machado A1 Nélio Gonçalves A1 Tiago M. Alfaro A1 Francisco Q. Gonçalves A1 Inês M. Araújo A1 Joana I. Real A1 Joana E. Coelho A1 Geanne M. Andrade A1 Ramiro D. Almeida A1 Jiang-Fan Chen A1 Attila Köfalvi A1 Paula Agostinho A1 Rodrigo A. Cunha YR 2018 UL http://www.eneuro.org/content/5/6/ENEURO.0385-18.2018.abstract AB Neurodegeneration 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 A2A receptors (A2AR), 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 A2AR control convulsions-induced hippocampal neurodegeneration. The pharmacological or genetic blockade of A2AR did not affect kainate-induced convulsions but dampened the subsequent neurotoxicity. This neurotoxicity began with a rapid A2AR upregulation within glutamatergic synapses (within 2 h), through local translation of synaptic A2AR mRNA. This bolstered A2AR-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 A2AR selectively in forebrain neurons. This shows that synaptic A2AR critically control synaptic excitotoxicity, which underlies the development of convulsions-induced neurodegeneration.