Circadian Regulation of Neural Excitability in Temporal Lobe Epilepsy

Epilepsy is the single most common serious brain disorder in every country of the world and is also one of the most universal of all medical disorders, affecting all ages, races, social classes, and nations (Janca et al. 1997). Among the 40 epileptic clinical syndromes, temporal lobe epilepsy (TLE) is the most common chronic partial epilepsy, affecting nearly 50 million people worldwide. TLE is a heterogeneous disorder and is thought to develop via a cascade of dynamic biological events that alter the balance between excitation and inhibition in limbic neural networks. Although it is not yet clear which mechanisms are necessary or sufficient for the development of epilepsy, a number of recent studies have provided evidence for circadian rhythmicity in the occurrence of seizures, both in humans and in animal models of chronic epilepsy (Arida et al.; Quigg et al. 1998, 2000; Herman et al. 2001; Hofstra and de Weerd 2009; Hofstra et al. 2009). Several factors are thought to contribute to the pattern of seizure recurrence, such as state-dependent changes in neuronal excitability associated with the sleep–wake cycle, daily rhythms of hormone release, and body temperature (Quigg et al. 1998, 2001; Herman et al. 2001). This work is motivated by the fact that very limited information is available to correlate in vivo limbic neural excitability changes with circadian factors in epilepsy. Preliminary experiments coupled with computational modeling have generated novel hypotheses for circadian control of neural excitability in epilepsy (Talathi et al. 2009). We focus our attention on CA1 because its cell properties have been so extensively studied in normal and epileptic brain; CA1 cells are often referred to as the “model” CNS neuron. Spontaneous sharp wave (SW) CA1 activity is employed to evaluate large-scale hippocampus synaptic activity and neural excitability. These studies are then evaluated in the setting of the circadian cycle. Forced desynchrony experiments are employed in order to establish a role for the circadian timekeeper with regard to CA1 neural excitability. Our results suggest that the acutely induced seizures perturb the phase relationship of SW activity within the CA1 region with respect to the circadian rhythm. The resulting perturbation in phase appears to produce an imbalance in the firing dynamics, such that the network within the hippocampus becomes increasingly excitable, eventually leading to spontaneous epileptic limbic seizures. Based Please provide publication date for Arida et al. here and in the reference list. contents