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

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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 24 h in the DG of epileptic rats (n=8) 8 weeks 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 2 p.m. and 10 p.m. and a low-seizure phase between 10 p.m. and 2 p.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) 25 ms, p=0.003; IPI 30 ms; p<0.001) but not in the high-seizure phase. Similarly, when compared to controls, inhibition at IPI 20 ms 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.

Highlights

▸In human and rat temporal lobe epilepsy, seizure occurrence peaks in late afternoon. ▸In a rat model, circadian change of dentate gyrus excitability was assessed hourly. ▸Electrophysiology shows neuronal hyperexcitability when seizure manifestation peaks. ▸These findings may explain circadian seizure distribution in temporal lobe epilepsy.

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