Abstracts

Abnormal thalamocortical rhythmicity contributes to absence epilepsy. Essential for such rhythmicity are inhibitory connections from neurons of the thalamic reticular nucleus (TRN) to thalamocortical relay cells (TC), while inhibitory connections within TRN are thought to suppress such activities. In an attempt to identify which GABA[sub]A[/sub]-receptor subunits within the thalamus contribute to absence seizure genesis or antagonism and allow for therapeutic targeting, we applied a combination of pharmacological and genetic approaches to characterize the nucleus-specific role of the [alpha]3 subunit.
Whole-cell voltage clamp recordings were obtained from TRN and TC neurons in slices of P10-P15 wild-type (WT) and [alpha]3 (H126R) mutant mice (Rudolph et al., 1999, Nature 401:796-800) to study GABA[sub]A[/sub]-receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSCs), isolated by appropriate pharmacological treatment. The [alpha]1 selective benzodiazepine (BZ) agonist zolpidem (ZL, 100 nM) was locally applied. Extracellular multiunit recordings of thalamic oscillations were made in 400 [mu]m thick horizontally sectioned slices from P12-P20 mice. Oscillations were evoked by 7 [ndash] 70 V stimuli delivered through a bipolar electrode.
In TRN cells, ZL increased the weighted decay time constant ([tau][sub]d,w[/sub]) by 30% (p[lt]0.05; n = 5) in WT, but not in the [alpha]3 (H126R) mutant. By contrast, in TC cells, which express the [alpha]1 subunit, [tau][sub]d,w[/sub] was increased up to 70% (p[lt]0.05; n = 7), with no difference in enhancement between WT and mutant mice (p[gt]0.05). Using multi-unit extracellular recordings of GABA[sub]A[/sub]-receptor dependent evoked oscillations, we found that ZL (500[ndash]1000 nM ) significantly shortened the period of oscillations in [alpha]3 (H126R) mutant mice (mean reduction = 10 msec; p [lt] 0.01; n = 10) and significantly decreased synchrony, as measured by the oscillatory index (mean reduction = 33%; p [lt] 0.05; n = 10). ZL had no significant effect on the spike count during these oscillations.
The modulation of IPSCs in TC but not TRN neurons in the [alpha]3 (H126R) mutant indicates that potentiation of IPSCs by BZs and related compounds is ultimately dependent on the presence of the [alpha]3 subunit in TRN, whereas in TC presumably the [alpha]1 subunit provides the major contribution. The effects of ZL on evoked thalamic oscillations in [alpha]3 (H126R) mutant mice must therefore depend on a mechanism other than enhancement of inhibitory synapses between TRN neurons (Sohal et al., [italic]J Neurosci[/italic], 2003). This suggests that the reductions we observed in the period and synchrony of evoked oscillations result from the potentiation of IPSCs in TC neurons and indicates a novel GABA[sub]A[/sub]- receptor dependent mechanism for regulation of epileptiform synchrony in thalamocortical circuits.
[Supported by: NINDS]