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.

Adenosine kinase and adenosine receptors A1R and A2AR in temporal lobe epilepsy and hippocampal sclerosis and association with risk factors for SUDEP

“…Epilepsy is associated with altered cellular distribution of adenosine receptors and ADK that may occur as primary or secondary adaptive phenomena 1,2 . Earlier studies utilizing human tissues found enhanced neuronal expression of A 1 R 21 and upregulation of A 2A R in Rasmussen's encephalitis, with A 2A R expression in lesional astrocytes, endothelium, as well as neurons 5 .…”

“…Adenosine has varied physiological functions in the central nervous system (CNS) including endogenous anticonvulsant actions. Although not a conventional neurotransmitter, its binding with high affinity G protein–coupled presynaptic and postsynaptic receptors (A 1 R and A 2A R) modulates synapses with predominantly inhibitory and neuroprotective effects 1,2 . Adenosine levels rise before seizure termination 2,3 ; activation of hyperpolarizing presynaptic A 1 R suppresses seizures and their spread, whereas A 1 R‐selective antagonists reverse this effect 2 .…”

“…Adenosine levels rise before seizure termination 2,3 ; activation of hyperpolarizing presynaptic A 1 R suppresses seizures and their spread, whereas A 1 R‐selective antagonists reverse this effect 2 . By contrast, A 2A R neuronal activation has mainly proconvulsive actions 1…”

“…Alteration in adenosine receptors densities and their cellular distribution has been shown in animal models of epilepsy1,2 and human tissues 4‐6 . An imbalance between the inhibitory and excitatory effects of adenosine through differential activation of A 1 R and A 2A R receptors may contribute to temporal lobe epilepsy (TLE) 4 .…”

Hyperthermia‐induced seizures produce long‐term effects on the functionality of adenosine A1 receptor in rat cerebral cortex

“…Nowadays, it is widely recognized that the activation of A 1 R and A 2A R both exerts anticonvulsant effects in the brain and controls neuronal damage after convulsions, thus dampening epileptogenesis (Canas et al, ; El Yacoubi, Ledent, Parmentier, Costentin, & Vaugeois, ). We previously described the effect of HIS on A 1 R density in several brain regions (Crespo, León‐Navarro, & Martín, ; León‐Navarro, Albasanz, & Martín, ).…”