Abstracts

Rationale: Acute changes following status epilepticus (SE) activate the JAK/STAT pathway (i.e., Janus Kinase / Signal Transducer and Activator of Transcription pathway) in the dentate gyrus (DG) of the hippocampus. JAK/ STAT pathway activation precedes ICER (i.e., inducible cAMP early repressor) and phosphorylated CREB (i.e., cAMP response element-binding protein) binding to the GABA_A receptor ?1 subunit (GABAR?1) CRE site which mediates decreased transcription of GABAR?1 after SE. The goal of these studies is to evaluate whether recent spontaneous seizures in chronically epileptic animals reactivate the JAK/STAT pathway to promote a subsequent reduction in the expression of GABAR?1 in the dentate gyrus (DG) of the hippocampus. Methods: Four weeks after SE was induced (and after baseline seizure frequency was established using continuous video-EEG monitoring), epileptic rats were sacrificed within 3 hours or more than 24 hours after a spontaneous seizure to determine mRNA or protein levels of pJAK2, pSTAT3, ICER and GABAR?1 in microdissected DG of hippocampus. Results: Significantly increased levels of pSTAT3 and decreased levels of GABAR?1 are expressed in the DG within 3 hours of a spontaneous seizure in rats 4 weeks after SE relative to control rats that received a subconvulsive dose of pilocarpine, did not experience SE, and did not have spontaneous seizures (p<0.05). By contrast, epileptic rats that did not have any spontaneous seizures within 24 hours of sacrifice showed no change in pSTAT3 or GABAR?1 expression relative to controls. Rats sacrificed within 3 hours of a seizure had significantly higher pSTAT3 expression and reduced GABAR?1 expression when compared to those animals sacrificed more than 24 hours after a spontaneous seizure. Correlated seizure frequencies demonstrate that rats sacrificed within 3 hours of a seizure had a higher seizure frequency than the group that failed to have a seizure within 24 hours of sacrifice. Conclusions: Taken together, these preliminary data suggest that the spontaneous, recurrent seizures that define chronic epilepsy may reactivate the JAK/STAT pathway and its downstream sequelae of GABAR?1 regulation. These distinctive properties suggest that JAK/STAT inhibitors may potentially be a novel addition to current therapy for refractory seizures, which occur in ~40% of temporal lobe epilepsy patients.