Circadian dentate gyrus excitability in a rat model of temporal lobe epilepsy

Abstract

In human mesial temporal lobe epilepsy (mTLE), seizure occurrence peaks in the late afternoon and early evening. This temporal binding of seizures has been replicated in animal models of mTLE following electrically-induced status epilepticus (SE). We hypothesized that in chronic epilepsy, alterations of circadian excitatory and inhibitory functions of the dentate gyrus (DG), which is believed to regulate the generation of limbic seizures, pathophysiologically contribute to the temporal binding of ictogenesis. We performed electrophysiological single and paired pulse measurements hourly over 24h in the DG of epileptic rats (n=8) 8weeks after electrically induced SE. Results were compared to individual data obtained before induction of SE and to those of control animals (n=3). Pre and post SE data were analyzed in two distinct phases of the day, i.e. a high-seizure phase between 2p.m. and 10p.m. and a low-seizure phase between 10p.m. and 2p.m. In chronic epileptic animals, latency of evoked potentials was significantly reduced in the high-seizure phase (p=0.027) but not in the low-seizure phase. Compared to baseline values, paired pulse inhibition was significantly increased during the low-seizure phase (interpulse interval (IPI) 25ms, p=0.003; IPI 30ms; p<0.001) but not in the high-seizure phase. Similarly, when compared to controls, inhibition at IPI 20ms was diminished only in the high-seizure phase (p=0.027). Thus, in chronic epileptic animals, DG excitability is increased in the afternoon and early evening possibly contributing to the time of day-dependency of spontaneous seizures in this model system of mTLE. Alterations of circadian DG excitability in epileptic animals may be influenced by changes in hypothalamus-regulated superordinate functions such as excretion of endocrine hormones but further studies are needed.