Adenosine Release during Seizures Attenuates GABA_AReceptor-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 patchclamp 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.

The Antiepileptic Potential of Nucleosides

“…The antiseizure role of A 1 receptors was recently strengthened because (i) A 1 receptor knockout mice showed spontaneous hippocampal seizures and high sensitivity to status epilepticus [282,283] and (ii) seizure-activity-limiting effects of Ado (A 1 receptor)-induced attenuation of depolarizing GABA A receptor signaling has been demonstrated [284]. In addition, CCPA enhanced the antiseizure effect of carbamazepine in the mouse maximal electroshock seizure model [285].…”

Glial adenosine kinase – A neuropathological marker of the epileptic brain

“…On the post-synaptic membrane of excitatory neurons, A 1 R modulates the activity of inwardly rectifying K+ channels, which can directly stabilize the membrane potential or hyperpolarize the cell (Luscher et al, 1997; Takigawa and Alzheimer, 2002). Recently, the A 1 R has also been found to reduce GABA A -receptor dependent depolarizations that occur during a seizure (Ilie et al, 2012). Thus, A 1 R modulation of network excitability has the capability to exert a profound anticonvulsant effect.…”

Cell-attached recordings of responses evoked by photorelease of GABA in the immature cortical neurons

“…This indicates that voltage-dependent changes in the intracellular chloride concentration are highly dynamic and may occur as a result of chloride flow via tens of GABA channels [comparable with ~thirty channels activated during unitary synaptic events (Edwards et al, 1990)] within hundreds of milliseconds. This corresponds to the hypothesis that intracellular chloride concentration is dynamically modified during physiological or paroxysmal activities so that chloride accumulates in synapses previously activated during strong cell depolarization (e.g., during spike trains or epileptic population spikes) (Kaila et al, 1997; Fujiwara-Tsukamoto et al, 2003, 2010; Ilie et al, 2012; for reviews, Isomura et al, 2008; Lamsa et al, 2010; Raimondo et al, 2012). An additional factor contributing to the hysteresis of GABA responses could be a change in the chloride concentration at the tip of the recording electrode.…”