Abstracts

Rationale: Circadian rhythms regulates nearly all biological functions. The core clock gene feedback loop is the molecular basis for circadian rhythms and is present in most cells. The core clock genes include the Circadian Locomotor Output Cycles Kaput (CLOCK), the Brain and Muscle ARNT-Like 1 (Bmal1), Period (Per) and cryptochrome (Cry) but their roles have not been investigated in chronic epilepsy. Here we investigated clock gene expression in the GAERS model of absence epilepsy and the kainic acid-induced post-SE model (KASE) of temporal lobe epilepsy (TLE).

Methods: Male GAERS (absence epilepsy) and NEC (non-epileptic control), KASE and sham (Wistar rats, non-epileptic) were kept in a 7am:7pm light-dark cycle. KASE had epilepsy induced at 11-weeks of age. Subdural EEG was acquired continuously for one week to establish diurnal seizure patterns and to correlate with clock gene expression. Animals were assigned to different timepoints (n=8/timepoint/strain) and tissue was collected starting from 7 am and every three hours throughout the day. At 20 weeks of age, when all GAERS have multiple seizures and KASE rats develop TLE; the hippocampus, hypothalamus, liver, and small intestine were collected. qPCR was performed to quantify mRNA expression of the core circadian clock genes Per1, Cry1, CLOCK, and Bmal1.

Results: In the GAERS rats, all the tissue exhibited significant changes in clock gene expression (p< 0.05) when compared to NEC. There were strong relationships between clock genes, seizure number, and duration in the hippocampus and small intestine (r >0.7). In the KASE rats, Cry1 and CLOCK were dysregulated in the hippocampus compared to controls (p < 0.05). Furthermore, a strong relationship was found in the liver of KASE rats between Per1 and number of seizures, and between Bmal1 and seizure duration and number of seizures.