EFFECTS OF BICUCULLINE AND BACLOFEN ON PAIRED-PULSE DEPRESSION IN THEDENTATE GYRUS OF EPILEPTIC PATIENTS

Paired-pulse field responses were recorded from the granule cell layer of the dentate gyrus in brain slices from temporal lobe epileptic pat ients. Paired-pulse depression (PPD) was examined using perforant path stimulation of low to moderate intensity at an inter-stimulus interva l (ISI) of 20 ms. The paired-pulse ratio (PS2/PS1) was expressed as th e population spike amplitude of the second response (PS2) relative to that of the first response (PS1). Representative tissue responses from each patient biopsy were divided into two groups that were significan tly different based on the magnitude of the highest paired-pulse ratio recorded for each biopsy specimen: the strong paired-pulse depression group (PS2/PS1 = 0.12 +/- 0.03; n = 15) and the weak paired-pulse dep ression group (PS2/PS1 = 0.68 +/- 0.06; n = 13). Paired-pulse ratios f rom the strong PPD group were relatively independent of stimulus inten sity, whereas, PPD was dependent on stimulus intensity in the weak PPD group; i.e., PPD was greatest at the lowest intensity and reached a p lateau at higher intensities. Bicuculline (20 mu M) and low concentrat ions of baclofen (0.1-0.2 mu M) reduced paired-pulse depression in the strong PPD group, but did not significantly change the paired-pulse r atio in the weak PPD group. Paired-pulse facilitation was observed in some cases after inhibition was blocked pharmacologically. The number of population spikes was increased in the presence of bicuculline but was unchanged by baclofen. In the strong PPD group, baclofen significa ntly altered the EPSP-population spike (E-S) relationship by increasin g the slope of the relationship for the second response, without havin g an effect on the slope of the first response. Baclofen had no effect on the E-S relationship of either response in the weak PPD group. The data are consistent with (1) less inhibition in the weak PPD group co mpared to the strong PPD group, (2) reduction of feedback inhibition i n the strong PPD group by bicuculline and by low concentrations of bac lofen, and (3) the occurrence of paired-pulse facilitation when inhibi tion was pharmacologically reduced in the dentate gyrus of temporal lo be epileptic patients. The results are also consistent with the presen ce of GABA(B) receptors on human inhibitory interneurons that, when ac tivated by baclofen, result in disinhibition of granule cells through feedback circuits. Although inhibition may be compromised in some epil eptic human biopsy specimens, the presence of strong inhibition in oth er patients' biopsy material suggests the re-evaluation of the role of inhibition in epilepsy.