Abstracts

RATIONALE: SE-induced alterations in the subunit composition of GABAA receptors (GABARs) may play a crucial role in increasing neuronal excitability thereby contributing to the subsequent development of spontaneous seizures. The present study determined whether the SE-induced changes in GABAR function and GABAR subunit mRNA levels, described previously in dentate granule cells (DGCs), reflects altered transcriptional control of the production of GABARs, or is due to changes in mRNA stability or processing. METHODS: The subunit was chosen for examination because it showed the strongest epilepsy-associated regulation. Transgenic mice carrying a lac-Z fusion gene driven by the GABAR subunit promoter were administered pilocarpine (PILO; 340 mg/kg). Ensuing SE was terminated at 2 hrs by diazepam (DZ). Controls received subconvulsive PILO and DZ. Animals were sacrificed 1, 5, and 6 days post-SE, and activity of the subunit promoter was monitored using standard histochemical techniques (X-Gal staining). RESULTS: Altered transcriptional regulation of the GABAR subunit occured in dentate gyrus (DG) in the first week post-SE. Control animals (N=2) expressed -galactosidase in DG, CA1, neocortex (NCtx), and thalamus (THAL), similar to subunit expression in vivo. In brains of 5 and 6 days post-SE mice(N=4), strongly reduced X-Gal staining was evident in DG, but not CA1, NCtx, or THAL. Decreased X-Gal staining was also evident in DG 24 hrs post-SE (N=2), but the level of decrease was less than that at 5 days post-SE. One animal in which PILO did not trigger SE had control levels of DG X-Gal staining. CONCLUSIONS: Control of the transcriptional machinery regulating expression of GABARs is modified during the latent period. Given that GABARs constitute one of the two primary neurotransmitter systems in the CNS, SE-induced changes in the transcriptional regulation of these proteins may be critical to subsequent seizure development. Understanding the nature of these SE-induced transcriptional alterations may provide novel avenues for therapeutic intervention in epileptogenesis. Support: NINDS NS-32403, NS-38572