Augmentation of Tonic GABAA Inhibition in Absence Epilepsy: Therapeutic Value of Inverse Agonists at Extrasynaptic GABAA Receptors
GHB and THIP enhance tonic GABAA currents in VB thalamus in vitro and induce SWDs in vivo. (a) Examples of SWDs in bilateral EEG traces recorded from Wistar rats following selective activation of eGABAARs by intrathalamic application of THIP via microdialysis (100 μM). The top trace shows seizures occurring in the first hour after THIP administration and the bottom the second hour. The spectrogram (corresponding to the right hemisphere of the lower traces) clearly shows an increase in oscillatory power in the 5–7 Hz range typical of SWDs in rats. The graph (right) summarises the concentration-dependent emergence of SWDs after THIP application as the total time spent in seizure during 20 minutes bins. (b) THIP produces robust enhancement of tonic GABAA currents in VB TC-neurons in acute brain slices in vitro. (c) GHB produces increased tonic current in VB TC neurons. (d) Graph summarising the concentration-dependent enhancement of thalamic tonic currents by GHB and the blocking effect of the GABABR antagonist CGP55845. (e) Block of GABABRs by CGP55845 produces a reduction of tonic GABAA currents in VB TC neurons of epileptic GAERS, stargazer, and lethargic mice. *, **, ***. Number of recorded neurons for each condition is indicated inset into bars. (a–e) reproduced from reference .
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