Abstracts

Hippocampal alterations of GABA[sub]A[/sub]/central benzodiazepine receptor (GABA[sub]A[/sub]/cBZR) expression are noted in TLE patients and animal models, but their importance to epileptogenesis is uncertain. The binding of the GABA[sub]A[/sub]/cBZR antagonist [³H]-Flumazenil was studied in the hippocampus of amygdala-kindled and kainate-treated rat models of [ldquo]early[rdquo] and [ldquo]later[rdquo] epileptogenesis Age-matched male Wistar rats were divided into amygdala-kindling (n=5), kainate-treated (n=4) and control (n=6) groups. All kainate-treated rats were confirmed to have spontaneous seizures and all kindled rats attained 5 ClassV seizures. GABA[sub]A[/sub]/cBZR density (Bmax) and affinity (Kd) were determined in all hippocampal strata from saturation-binding analysis using [³H]-Flumazenil. Mossy fiber sprouting into the dentate molecular layer and its relationship with Bmax was examined [underline]Kainate[/underline]-treated rats had bilateral [underline]decreased[/underline] Bmax in the oriens (78%), pyramidal (75%) and radiatum (79%) lamina of CA1 (all p[lt]0.05). A smaller reduction was seen in the dentate hilus (83%, p=0.06), and in the hilar insertion of CA3 (78% p=0.03). Contrastingly, the [underline]kindled[/underline] left hippocampus showed significantly [underline]increased[/underline] Bmax in all subregions except CA2 (all p[lt]0.05), with marked elevation in the dentate molecular layer (139%), CA1 molecular layer (128%) and stratum oriens of CA3 (134%). Mossy fiber sprouting was [underline]increased[/underline] in both kainate (197% p=0.01) and kindled (137%, p=0.01) groups, with a [underline]strong inverse correlation[/underline] between density of sprouted mossy fibers and GABA[sub]A[/sub]/cBZR expression in the dentate molecular layer (r=-0.84, p=0.004). No Kd changes were detected. The contrasting findings in the kindling and kainate-treated rats suggest that GABA[sub]A[/sub]/cBZR expression is [underline]upregulated[/underline] early in epileptogenesis, but [underline]downregulated[/underline] at the chronic epileptic phase in regions where cell loss occurs. Mossy fiber sprouting may modulate these changes which could represent an important compensatory or pathological mechanism in epileptogenesis