Abstracts

The beta-carbolines, such as the beta-CCM or methyl-beta-carboline-3-carboxylate, bind at the benzodiazepine site of the GABA-A receptor. This family has various effects, such as anxiogenic, learning/memory enhancement and convulsant effects.
Evidences suggest a genetic link between the mechanisms which control the seizuring response after a beta-carboline injection and those which control the absence-epilepsy: 1) it has been shown that the GAERS rats are more susceptible to seizures induced by a beta-carboline injection than the control NEpi rats; 2) two mouse lines derived from a bidirectionnal selection for their beta-CCM-induced-seizure susceptibility were characterized in our laboratory. These two strains differ logically for their beta-CCM response, but surprisingly they also differ for their electrophysiological activity: the susceptible one, BS/Orl, exhibits spontaneous, bilateral and synchronous spike and wave discharges (SWDs). The resistant one, BR/Orl, does not present any SWDs, even after injection of gamma-butyro-lactone, known to induce SWDs; 3) we created a pseudo-replicated selected line BS2/Orl for BS/Orl. These two lines share the same electrophysiological properties; 4) it has been shown that the Bis2 gene (beta-carboline-induced seizures 2), involved in beta-CCM responses, can modify the spontaneous SWD activity up to 600%. Our final goal is to identify genes involved in absence epilepsy. Since the genetic mechanisms for SWDs and beta-CCM response seem to overlap, we suggest in a first step to address the absence epilepsy genetic control in using the beta-CCM response trait. Here we present our mapping data and analysis for this beta-CCM induced seizure phenotype. The genome scan has been carried out on a segregating F2 population derived from BS/Orl and BR/Orl, with high density PCR markers using R-qtl (R package). Two chromosomal regions have shown a highly significant linkage on chromosome 1 between D1mit14 and D1mit353 and chromosome 5 between D5mit13 and D5mit308 (LOD=14 and 5, respectively; thresholds after permutations: p(0.05)= 3.19 and p(0.001)= 3.70). Mapping data and suggested candidate genes included in these regions are presented. (Supported by CNRS-France and the University of Orléans.)