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

Abstract

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.

• Authors: Paula M Canas, Lisiane O Porciúncula, Ana Patrícia Simões, Elisabete Augusto, Henrique B Silva, Nuno J Machado, Nélio Gonçalves, Tiago M Alfaro, Francisco Q Gonçalves, Inês M Araújo, Joana I Real, Joana E Coelho, Geanne M Andrade, Ramiro D Almeida, Jiang-Fan Chen, Attila Köfalvi, Paula Agostinho, Rodrigo A Cunha
• Journal: eNeuro (eNeuro) 2018 Nov-Dec Vol. 5 Issue 6 ISSN: 2373-2822 [Electronic] United States
• PMID: 30627646 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine
• Adenosine A2 Receptor Antagonists
• Convulsants
• Pyrimidines
• Receptor, Adenosine A2A
• Triazoles
• Kainic Acid

Topics

• Adenosine A2 Receptor Antagonists (therapeutic use)
• Amygdala (physiology)
• Animals
• Cells, Cultured
• Convulsants (toxicity)
• Epilepsy (complications, drug therapy, etiology)
• Hippocampus (drug effects, physiology)
• Kainic Acid (toxicity)
• Kindling, Neurologic (drug effects, physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nerve Degeneration (etiology, metabolism, prevention & control)
• Neurons (drug effects, metabolism)
• Protein Binding (drug effects)
• Pyrimidines (therapeutic use)
• Rats
• Rats, Wistar
• Receptor, Adenosine A2A (genetics, metabolism)
• Synaptic Transmission (drug effects, genetics)
• Triazoles (therapeutic use)