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Updated: May 29, 2026
Preparation and Implantation of Electrodes for Electrically Kindling VGAT-Cre Mice to Generate a Model for Temporal Lobe Epilepsy
Published on: August 17, 2021
Decreased CREB levels suppress epilepsy
Xinjian Zhu1, Xiao Han, Julie A Blendy
1The Children's Hospital of Philadelphia, Division of Neurology, USA.
Abstract:
Epilepsy is a common neurologic disorder yet no treatments aimed at preventing epilepsy have been developed. Several molecules including genes containing cAMP response elements (CREs) in their promoters have been identified that contribute to the development of epilepsy, a process called epileptogenesis. When phosphorylated cAMP response element binding protein (CREB) increases transcription from CRE regulated promoters. CREB phosphorylation is increased in rodent epilepsy models, and in the seizure onset region of humans with medically intractable epilepsy (Rakhade et al., 2005; Lee et al., 2007; Lund et al., 2008). Here we show that mice with decreased CREB levels (CREB(α∆) mutants) have a ~50% reduction in spontaneous seizures following pilocarpine induced status epilepticus (SE) and require more stimulation to electrically kindle. Following SE, brain derived neurotrophic factor (BDNF) and inducible cAMP early repressor (ICER) mRNAs are differentially up-regulated in the hippocampus and cortex of the CREB(α∆) mutants compared to wild-type mice, which may be contributing to differences in the severity of epilepsy. In contrast, we found no difference in KCC2 mRNA levels between the CREB(α∆) and wild-type mice after SE. The mechanism by which BDNF and ICER mRNAs increase specifically in the CREB(α∆) compared to wild-type mice following SE is not known. We did, however, find an increase in specific cAMP response element modulator (CREM) mRNA transcripts in the CREB(α∆) mutants that might be responsible for the differential regulation of BDNF and ICER after SE. Altering CREB activity following a neurologic insult provides a therapeutic strategy for modifying epileptogenesis.
Insights
Reducing cAMP response element binding protein (CREB) levels significantly decreased seizures in a mouse epilepsy model. This suggests targeting CREB activity may offer a new therapeutic strategy for preventing epilepsy development.
Area of Science:
- Neuroscience
- Molecular Biology
- Epilepsy Research
Background:
- Epilepsy is a common neurological disorder with no preventative treatments.
- Genes with cAMP response elements (CREs) are implicated in epileptogenesis.
- Phosphorylated cAMP response element binding protein (CREB) regulates transcription from CREs and is elevated in epilepsy models and human epilepsy.
Purpose of the Study:
- To investigate the role of CREB in epileptogenesis.
- To determine if reducing CREB levels impacts seizure severity and development.
- To explore molecular changes associated with altered CREB activity following a neurological insult.
Main Methods:
- Utilized CREB(α∆) mutant mice with reduced CREB levels.
- Induced status epilepticus (SE) using pilocarpine.
- Assessed seizure frequency and electrical kindling thresholds.
- Quantified mRNA levels of brain-derived neurotrophic factor (BDNF), inducible cAMP early repressor (ICER), and KCC2 in the hippocampus and cortex.
Main Results:
- CREB(α∆) mutant mice exhibited a ~50% reduction in spontaneous seizures post-SE and required more stimulation for kindling.
- Following SE, BDNF and ICER mRNAs were differentially upregulated in CREB(α∆) mutants compared to wild-type mice.
- No difference in KCC2 mRNA levels was observed between genotypes after SE.
- Increased cAMP response element modulator (CREM) mRNA transcripts were found in CREB(α∆) mutants, potentially explaining differential BDNF and ICER regulation.
Conclusions:
- Decreased CREB levels confer significant protection against seizures and epileptogenesis.
- Differential regulation of BDNF and ICER by CREM may underlie the reduced seizure susceptibility in CREB(α∆) mutants.
- Modulating CREB activity presents a potential therapeutic avenue for preventing epilepsy following neurological insults.
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