The Molecular Genetic Interaction Between Circadian Rhythms and Susceptibility to Seizures and Epilepsy

Abstract

Seizure patterns observed in patients with epilepsy suggest that circadian rhythms and sleep/wake mechanisms play some role in the disease. This review addresses key topics in the relationship between circadian rhythms and seizures in epilepsy. We present basic information on circadian biology, but focus on research studying the influence of both the time of day and the sleep/wake cycle as independent but related factors on the expression of seizures in epilepsy. We review studies investigating how seizures and epilepsy disrupt expression of core clock genes, and how disruption of clock mechanisms impacts seizures and the development of epilepsy. We focus on the overlap between mechanisms of circadian-associated changes in SCN neuronal excitability and mechanisms of epileptogenesis as a means of identifying key pathways and molecules that could represent new targets or strategies for epilepsy therapy. Finally, we review the concept of chronotherapy and provide a perspective regarding its application to patients with epilepsy based on their individual characteristics (i.e., being a "morning person" or a "night owl"). We conclude that better understanding of the relationship between circadian rhythms, neuronal excitability, and seizures will allow both the identification of new therapeutic targets for treating epilepsy as well as more effective treatment regimens using currently available pharmacological and non-pharmacological strategies.

The role of sleep state and time of day in modulating breathing in epilepsy: implications for sudden unexpected death in epilepsy

“…The circadian influence on seizures may be due in part to the bi-directional relationship of epilepsy and clock genes. Alterations in clock mechanisms increase the susceptibility for epilepsy, while seizures have the potential to disrupt the internal clock (Re et al, 2020 ). A significantly higher current is required to induce both maximal and generalized seizures in wild type (WT) mice during the dark phase of their diurnal cycle compared to the light phase.…”

From Physiology to Pathology of Cortico-Thalamo-Cortical Oscillations: Astroglia as a Target for Further Research

“…Moreover, the pathological activation of the mTOR pathway involved in LPS-induced increase in SWDs ( 265 , 266 ) is responsible for the upregulation of the core clock gene product aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL), also known as brain and muscle ARNT-Like 1 (BMAL1), as observed in a model of tuberous sclerosis complex, a neurological disorder displaying epileptic activity ( 333 ). BMAL1 not only is a key component of both circadian and sleep/wake cycles ( 334 ) as well as susceptibility to seizures and epilepsy ( 335 ), but it is also at the basis of cell-autonomous circadian clock of astrocytes ( 336 , 337 ).…”

“…Given the fact that both SWDs and NREM recruit the cortico-thalamo-cortical network, further insights into the role of astrocytes in the pathophysiology of SWDs may derive from evidence in their contribution to sleep (particularly sleep architecture and sleep/wake cycle) ( Figure 5 ) as well as the circadian cycle. Astroglial impact on circadian clock mechanisms generated in deep structures may contribute to epilepsy in non-intuitive ways ( 335 ). In the hypothalamic primary timekeeping center, the suprachiasmatic nucleus (SCN), astrocyte-derived glutamate inhibits neuronal firing through presynaptic NMDA receptors specifically during the night ( 338 ).…”

Circadian/multidien Molecular Oscillations and Rhythmicity of Epilepsy (MORE)

“…Given the circadian rhythmicity of seizures, it is tempting to link seizures to the genes and molecules that drive molecular oscillations 100,101 . Although there is no apparent cell loss in the SCN in the pilocarpine 102 and kindling 103 seizure models; light‐induced c‐Fos immunoreactivity is disrupted in the pilocarpine model, 104 perhaps signaling a defect in the daily phase resetting of the SCN clock.…”