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 Canas, Paula M.
A1 Porciúncula, Lisiane O.
A1 Simões, Ana Patrícia
A1 Augusto, Elisabete
A1 Silva, Henrique B.
A1 Machado, Nuno J.
A1 Gonçalves, Nélio
A1 Alfaro, Tiago M.
A1 Gonçalves, Francisco Q.
A1 Araújo, Inês M.
A1 Real, Joana I.
A1 Coelho, Joana E.
A1 Andrade, Geanne M.
A1 Almeida, Ramiro D.
A1 Chen, Jiang-Fan
A1 Köfalvi, Attila
A1 Agostinho, Paula
A1 Cunha, Rodrigo A.
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.