Abstracts

In a previous study (Sohal et al., [italic]J Neurosci[/italic], 2003) we demonstrated that clonazepam (CLZ) lacks efficacy in the suppression of abnormal in vitro thalamocortical rhythmicity in mice carrying a point mutation in the [alpha]3 subunit. Here we examined the effect of two anti-absence medications Ethosuximide (ES) and CLZ on EEG changes in the low dose pentylenetetrazole (PTZ) mouse model of Absence Epilepsy (AE). P35 wild-type (WT) and [alpha]3(H126R) mutant mice (Rudolph et al., Nature, 1999) were implanted for chronic EEG recording via three trans-calvarium screws wired to a pedestal connection. PTZ (40mg/kg) was administered alone or with CLZ (0.03 mg/kg) or ES (150 mg/kg), all via intraperitoneally injection. In addition whole-cell voltage clamp recordings were obtained from thalamic reticular neurons (TRN) and thalamocortical relay cells (TC) in slices of P6-P17 WT and [alpha]3(H126R) mutant mice to study the effect of CLZ (100 nM) and Zolpidem (ZLP, 100 nM) on GABA[sub]A [/sub]receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSCs), isolated by appropriate pharmacological treatment. While EEG recordings in WT mice revealed that both ES and CLZ decreased PTZ induced spike wave discharges (ES: 93 % reduction, CLZ: 55%) ES delayed seizure onset (by 17%). By contrast, in the [alpha]3(H126R) mutant, CLZ failed to block epileptic discharge while ES efficacy was unaffected. In patch-clamp recordings from WT TRN cells, CLZ and ZLP prolonged the weighted decay time constant ([tau][sub]d,w[/sub]) of sIPSCs by 40 % and 30%, respectively, but not in the mutant, whereas no difference in enhancement between WT and mutant mice could be seen in TC cells, which do not express [alpha]3. The inability of CLZ to control in vivo seizure activity in the [alpha]3 mutant demonstrates that the GABA[sub]A [/sub]receptor [alpha]3 subunit is the site of antiepileptic action for benzodiazepines (BZ). These EEG results are consistent with the fact that neither CLZ nor ZLP could enhance GABA[sub]A [/sub]receptor mediated sIPSCs in [alpha]3 mutant TRN neurons in whole cell recordings. Our findings uncover the unique role of the GABA[sub]A [/sub]receptor [alpha]3 subunit, most likely within the thalamic reticular nucleus, for the efficacy of BZs and related compounds in the treatment of AE. (Supported by the NINDS and FWF (Austrian Science Fund).)