Abstracts

Generation and propagation of epileptiform activity are highly dependent on the integrity of GABAergic inhibitory circuits. Phasic and tonic inhibitions are mediated by GABA[sub]A[/sub] receptors with different affinities for GABA, and can be blocked respectively by low and high concentrations of the specific GABA[sub]A[/sub] receptor antagonist SR95531. Phasic inhibition can be reduced by about 70% by 200 nM SR95531 without any effect on tonic inhibition (Stell [amp] Mody, 2002). Here we report that this concentration of SR95531 is the threshold to cause spontaneous epileptiform activity in the CA3 region.
Horizontal and coronal brain slices (350 [mu]m thick) were prepared from male C57Bl mice and a small surgical incision was made in the slices to severe the connections between CA3 and CA1. Stimulus-triggered and continuous field recordings were obtained from areas CA1 and CA3 of the hippocampus at 34-36[deg]C in aCSF, followed after 20 minutes by perfusion of 50 nM SR95531 and consequently, after another 20 minutes by perfusion of 200 nM SR95531. Recordings were low-pass filtered at 3 kHz and digitized at 10 kHz. Amplitudes of evoked events, coast-line indices, and total duration of epileptiform events constituted the measured parameters.
Normalized average coast-line index measurements in the CA1 region were 102.74[plusmn] 4.72% of control for 50 nM SR95531 and 110.61 [plusmn] 10.39% for 200 nM SR95531; in the CA3 region the values were 101.38 [plusmn] 2.89% for 50 nM SR95531 and 101.90 [plusmn] 6.08% for 200 nM SR95531. Spontaneous bursting was found in 5 out of 12 slices perfused with 200 nM SR95531 with a mean duration of 126 [plusmn] 57.34 ms and none in aCSF or with 50 nM SR95531. Multiple spiking was seen in aCSF (3/12 slices, mean duration 32.81 [plusmn] 13.52 ms), 50 nM SR95531 (5/12 slices, mean duration 27.46 [plusmn] 8.52 ms) and 200 nM SR95531 (7/12 slices; mean duration 33.11 [plusmn]17.74 ms). Bursting and multiple spiking were not seen in CA1 region.
Without any changes in tonic inhibition, a significant reduction in phasic inhibition of nearly 70%, as that produced by 200 nM SR95531, is necessary to elicit spontaneous epileptic bursts in the CA3 region, but not in the isolated CA1 region. These results suggest that tonic inhibition must play an important antiepileptic role when a considerable fraction of phasic inhibition becomes impaired.
[Supported by: NS 02808 and the Coelho Endowment]