Abstract
Adenosine is an inhibitory neuromodulator that exerts antiepileptic effects in the brain and the entorhinal cortex (EC) is an essential structure involved in temporal lobe epilepsy. Whereas microinjection of adenosine into the EC has been shown to exert powerful antiepileptic effects, the underlying cellular and molecular mechanisms in the EC have not been determined yet. We tested the hypothesis that adenosine-mediated modulation of synaptic transmission contributes to its antiepileptic effects in the EC. Our results demonstrate that adenosine reversibly inhibited glutamatergic transmission via activation of adenosine A1 receptors without effects on GABAergic transmission in layer III pyramidal neurons in the EC. Adenosine-induced depression of glutamatergic transmission was mediated by inhibiting presynaptic glutamate release probability and decreasing the number of readily releasable vesicles. Bath application of adenosine also reduced the frequency of the miniature EPSCs recorded in the presence of TTX suggesting that adenosine may interact with the exocytosis processes downstream of Ca2+ influx. Both Gαi/o proteins and the protein kinase A pathway were required for adenosine-induced depression of glutamatergic transmission. We further showed that bath application of picrotoxin to the EC slices induced stable epileptiform activity and bath application of adenosine dose-dependently inhibited the epileptiform activity in this seizure model. Adenosine-mediated depression of epileptiform activity was mediated by activation of adenosine A1 receptors and required the functions of Gαi/o proteins and protein kinase A pathway. Our results suggest that the depression of glutamatergic transmission induced by adenosine contributes to its antiepileptic effects in the EC.
Highlights
The entorhinal cortex (EC) mediates the majority of connections between the hippocampus and other cortical areas [1,2]
These results unanimously indicate that adenosineinduced depression of AMPA EPSCs is mediated via activation of A1 adenosine receptors (ARs) in the EC
Whereas the EC is an indispensable structure involved in the generation and propagation of epilepsy and adenosine is an endogenous antiepileptic substance, the cellular and molecular mechanisms of adenosine in modulating neural activity in the EC have not been determined
Summary
The entorhinal cortex (EC) mediates the majority of connections between the hippocampus and other cortical areas [1,2]. Neurons in the deep layers of the EC relay a large portion of hippocampal output information back to the superficial layers [7,8,9,10] and to other cortical areas [1]. Adenosine interacts with 4 subtypes of G protein-coupled adenosine receptors (ARs) that include A1, A2A, A2B and A3 [20,21,30,31]. Activation of A1 ARs activates phospholipase A2 and phospholipase D whereas A2B and A3 receptors increase the function of phospholipase C [21]. The biological functions of adenosine are likely to be mediated by these receptors
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