Adenosine Release during Seizures Attenuates GABAAReceptor-Mediated Depolarization

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 GABAAreceptor (GABAAR) 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 GABAAR signaling in pyramidal neurons of rat hippocampus. Consistent with previous reports, GABAAR responses during seizure activity transiently switched from hyperpolarizing to depolarizing and excitatory. We found that adenosine released during the seizure significantly attenuated the depolarizing GABAAR 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 GABAARs, or by a change in the conductance of GABAARs. Rather, A1R-dependent activation of potassium channels increased the cell's membrane conductance and thus had a shunting effect on GABAAR currents. As depolarizing GABAAR signaling has been implicated in seizure initiation and progression, the adenosine-induced attenuation of depolarizing GABAAR signaling may represent an important mechanism by which adenosine can limit seizure activity.