Abstracts

Rationale: To prevent the morbidity and mortality associated with the epilepsy we need to better understand the molecular and cellular mechanisms that contribute to the development of epilepsy. Several lines of evidence suggest that cAMP response element-binding protein (CREB) might be involved in the development of epilepsy. Over expression of a chronically active form of CREB causes epilepsy (Lopez de Armentia et al. 2007), over expression of (Inducible Cyclic AMP early repressor) ICER an inhibitor of CREB function can block the development of epilepsy(Kojima et al. 2008) and mice that lack ICER develop more severe epilepsy following status epilepticus(Porter et al. 2008). Here we have asked if mice deficient in CREB have a difference in epileptogenesis following status epilepticus (SE) or kindling. Methods: In this study, the chemoconvulsant pilocarpine and kindling model were used to investigate the role of CREB in the development of epilepsy. CREB αΔ mutant mice lack the α and Δ isoforms of CREB protein, resulting in the marked reduction of protein levels to ~15% of control levels. In the pilocarpine SE model, we recorded continuous video EEG in CREBαΔ mutant mice and wild type littermates during and following pilocarpine induced status SE to determine if CREB deficiency altered the development of epilepsy. In the kindling model animals implanted with a bipolar electrodes into the amygdala underwent daily electrical stimulation and after discharges as well as behavioral seizures were quantified. Results: Pilocarpine SE: Decreased CREB activity did not change the number of animals that developed epilepsy or SE duration, but significantly reduced the spontaneous seizure frequency following the episode of SE (spontaneous seizures/hour WT: 0.062±0.011; CREBαΔ mutant: 0.033±0.003). The latency to onset of SE and spontaneous seizures did not show a significant difference between the WT and CREBαΔ mutant mice. Kindling: The current required to evoke the initial electrographic seizure was similar in both WT and CREBαΔ mutant mice. However, the CREBαΔ mutant mice required significantly more electric stimulations to reach stage 2, 3, 4 and 5 behavioral seizures as compared to that of WT mice. The electrographic seizure duration, after discharges, did not show a difference between the genotypes. Conclusions: CREB deficient mice had suppressed epileptogenesis in the pilocarpine and kindling models, suggesting that blocking CREB activity following a brain insult may prevent or mitigate epilepsy. Future studies are directed at trying to understanding the downstream targets of CREB that contribute to epilepsy, and if blocking CREB mediated transcription after an episode of SE can alter epileptogenesis. This work was supported by NINDS and CURE.