Neuronal Adenosine A2A Receptors Are Critical Mediators of Neurodegeneration Triggered by Convulsions

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 A(2A) receptors (A(2A)R), 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(2A)R control convulsions-induced hippocampal neurodegeneration. The pharmacological or genetic blockade of A(2A)R did not affect kainate-induced convulsions but dampened the subsequent neurotoxicity. This neurotoxicity began with a rapid A(2A)R upregulation within glutamatergic synapses (within 2 h), through local translation of synaptic A(2A)R mRNA. This bolstered A(2A)R-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(2A)R selectively in forebrain neurons. This shows that synaptic A(2A)R critically control synaptic excitotoxicity, which underlies the development of convulsions-induced neurodegeneration.