Abstracts

Rationale: Epilepsy is a highly prevalent neurological disorder defined by the emergence of recurring, spontaneous seizures. Current anticonvulsant medications do not prevent epileptogenesis, and we believe that elucidation of long-term gene expression changes in the epileptic brain will be instrumental in the development of truly anti-epileptogenic treatments. We previously identified the histone methylase EZH2 as a principal driver of gene expression changes in rodent dentate granule cells after induction of Status Epilepticus (SE).

Methods: We utilized state of the art bioinformatic approaches to mine RNAseq profiles of naïve, epileptic, wild type and conditional knockout mice.  Predictions were tested in vivo using biochemical, molecular biological and physiological techniques to assess gene changes, alterations in protein levels and seizure threshold in mouse models of status epilepticus and epileptogenesis.

Results: We report here that EZH2 protein is induced chronically in hippocampal neurons. Upon conditional knockout of EZH2 in neurons, we observe a robust reduction in the flurothyl seizure threshold of mice after SE. This occurs in the absence of threshold changes in naïve mice and in the absence of changes to seizure severity during SE.  This suggests that EZH2 induction post SE is a protective mechanism invoked during seizures.

Whole hippocampus RNAseq analysis suggests that EZH2 targets a number of pro-epileptogenic signal transduction pathways including the JAK/STAT pathway. Consistent with this, we report that whereas wild-type mice show a transient induction of the JAK/STAT pathway post SE, loss of EZH2 results in sustained induction of this pathway.

Conclusions: In summary we find that EZH2 induction after SE is a protective mechanism that acts to temper pro-epileptic signal transduction pathways.

Funding: Please list any funding that was received in support of this abstract.: This work was supported by CURE, NIH and Lily's Fund.