Epilepsy is a chronic neurological disease characterized by the recurrent of spontaneous seizures in behavior. Temporal lobe epilepsy (TLE) is most common and drug-resistant type of adult focal epilepsy. To understand the mechanism underlying epileptogenesis, we explored the role of transcription repressor neuron restrictive silence factor (NRSF) also named REST in epileptogenesis. (1), The expression of REST/NRSF is decreased after differentiation of neuron. However, it has been upregulated during seizures activity. The limbic epileptogenesis has been greatly accelerated when we conditionally knockout (cKO) REST/NRSF in excitatory neuron of forebrain in adult mice. This phenomenon accompanied with increased mossy fiber sprouting in cKO mice. Interesting, we did not find any significant difference of cell death between cKO and control mice in kindling and KA model. Subsequently, we found mRNA expression of four NRSF regulated target genes L1cam, FGF14, BDNF, TrkB significantly upregulated in cKO mice. (2), Recently, a literature report that glycolytic inhibitor 2-deoxy-D-glucose impaired epileptogenesis by recruiting CtBP dependent REST/NRSF suppressing complex to remodel chromatin structure. By conditional deletion of REST/NRSF, we found REST/NRSF mediated transcriptional repression is required for antiepileptic effect of 2DG, but not acetone and ketogenic diet. Taken together, these results indicated that REST/NRSF serves as an intrinsic suppressor in epileptogenesis and is required for antiepileptic effect of 2DG but not acetone and ketogenic diet.