title: Adenosine release during seizures attenuates GABAA receptor-mediated depolarization.
abstract: Seizure-induced release of the neuromodulator adenosine is a potent endogenous anticonvulsant mechanism, which limits the extension of seizures and mediates seizure arrest. For this reason several adenosine-based therapies for epilepsy are currently under development. However, it is not known how adenosine modulates GABAergic transmission in the context of seizure activity. This may be particularly relevant as strong activation of GABAergic inputs during epileptiform activity can switch GABA(A) receptor (GABA(A)R) signaling from inhibitory to excitatory, which is a process that plays a significant role in intractable epilepsies. We used gramicidin-perforated patch-clamp recordings to investigate the role of seizure-induced adenosine release in the modulation of postsynaptic GABA(A)R signaling in pyramidal neurons of rat hippocampus. Consistent with previous reports, GABA(A)R responses during seizure activity transiently switched from hyperpolarizing to depolarizing and excitatory. We found that adenosine released during the seizure significantly attenuated the depolarizing GABA(A)R responses and also reduced the extent of the after-discharge phase of the seizure. These effects were mimicked by exogenous adenosine administration and could not be explained by a change in chloride homeostasis mechanisms that set the reversal potential for GABA(A)Rs, or by a change in the conductance of GABA(A)Rs. Rather, A(1)R-dependent activation of potassium channels increased the cell's membrane conductance and thus had a shunting effect on GABA(A)R currents. As depolarizing GABA(A)R signaling has been implicated in seizure initiation and progression, the adenosine-induced attenuation of depolarizing GABA(A)R signaling may represent an important mechanism by which adenosine can limit seizure activity.
authors.affiliation: Department of Pharmacology, Oxford University, Oxford OX1 3QT, United Kingdom.
authors.forename: Andrei
authors.initials: A
authors.lastname: Ilie
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Raimondo
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Akerman
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D058907:Adenosine A1 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D056654:CA3 Region, Hippocampal / Q000166:cytology / Q000502:physiology; D002712:Chlorides / Q000378:metabolism; D004833:Epilepsy, Temporal Lobe / Q000473:pathology; D018755:GABA Agonists / Q000494:pharmacology; D006096:Gramicidin / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D009118:Muscimol / Q000494:pharmacology; D009431:Neural Conduction / Q000187:drug effects; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013779:Tetrodotoxin
chemical_list: D058907:Adenosine A1 Receptor Agonists; D002712:Chlorides; D018755:GABA Agonists; D011963:Receptors, GABA-A; D006096:Gramicidin; D009118:Muscimol; D013779:Tetrodotoxin; D000241:Adenosine