Augmentation of Tonic GABA_A Inhibition in Absence Epilepsy: Therapeutic Value of Inverse Agonists at Extrasynaptic GABA_A Receptors

Figure 1

GAT-1 transporter dysfunction produces enhanced tonic GABA_A currents in VB TC neurons in animal models of absence epilepsy. (a) The developmental profile of enhanced thalamic tonic current observed in GAERS animals compared to NEC. At P17 (prior to seizure onset), a significant increase in current amplitude is observed in the epileptic animal that remains elevated up to seizure onset (P30). (b) Tonic GABA_A currents in VB TC neurons of monogenic stargazer (stg) and lethargic (l hour) mice are significantly greater than nonepileptic littermates after seizure onset. (c) Block of GAT-1 using NO711 in NEC animals elevates tonic current amplitude to levels similar to those observed in GAERS animals. No further enhancement of tonic current in GAERS is observed when GAT-1 is blocked. Block of GAT-3 produces significant increases in tonic current in both NEC and GAERS animals although the increase is smaller in NEC where GAT-1 remains functional. Simultaneous block of GAT-1 and GAT-3 results in very large tonic currents in both GAERS and NEC animals, which are not significantly different from each other. (d) Graph summarising the experiments depicted in (c). (e) Graph depicting the same series of experiments performed in stargazer mice illustrating the similar effects in both models. *𝑃<0.05, **𝑃<0.01, ***𝑃<0.001. Number of recorded neurons for each condition is indicated in bars. (a–e) reproduced from [34].