BMAL1 controls the diurnal rhythm and set point for electrical seizure threshold in mice

Jason R Gerstner,Russell J Buono,Thomas N Ferraro,Olivia Lenz,Isaac J Perron,George G Smith

doi:10.3389/fnsys.2014.00121

Abstract

The epilepsies are a heterogeneous group of neurological diseases defined by the occurrence of unprovoked seizures which, in many cases, are correlated with diurnal rhythms. In order to gain insight into the biological mechanisms controlling this phenomenon, we characterized time-of-day effects on electrical seizure threshold in mice. Male C57BL/6J wild-type mice were maintained on a 14/10 h light/dark cycle, from birth until 6 weeks of age for seizure testing. Seizure thresholds were measured using a step-wise paradigm involving a single daily electrical stimulus. Results showed that the current required to elicit both generalized and maximal seizures was significantly higher in mice tested during the dark phase of the diurnal cycle compared to mice tested during the light phase. This rhythm was absent in BMAL1 knockout (KO) mice. BMAL1 KO also exhibited significantly reduced seizure thresholds at all times tested, compared to C57BL/6J mice. Results document a significant influence of time-of-day on electrical seizure threshold in mice and suggest that this effect is under the control of genes that are known to regulate circadian behaviors. Furthermore, low seizure thresholds in BMAL1 KO mice suggest that BMAL1 itself is directly involved in controlling neuronal excitability.

Highlights

Time-of-day factors such as sleep and circadian rhythms are well known to influence expression of seizures (Matos et al, 2010a; Cho, 2012)
In patients with common forms of idiopathic generalized epilepsy, tonic, and tonic-clonic seizures are more frequently seen in sleep, whereas all other generalized semiologic seizure types including clonic, myoclonic, absence and atonic occur more frequently out of wakefulness (Zarowski et al, 2011), suggesting circadian rhythms control distinct mechanisms of neuronal hyperexcitability that may result in seizures
Since generalized electroshock seizure threshold (GEST) and MEST values appeared lower during the light phase compared to the dark phase overall, we were interested in testing for the diurnal effects on seizure endpoints between these two groups

Summary

Introduction

Time-of-day factors such as sleep and circadian rhythms are well known to influence expression of seizures (Matos et al, 2010a; Cho, 2012). In patients with common forms of idiopathic generalized epilepsy, tonic, and tonic-clonic seizures are more frequently seen in sleep, whereas all other generalized semiologic seizure types including clonic, myoclonic, absence and atonic occur more frequently out of wakefulness (Zarowski et al, 2011), suggesting circadian rhythms control distinct mechanisms of neuronal hyperexcitability that may result in seizures. Sleep is associated with twice as many interictal discharges in patients with idiopathic generalized epilepsy, especially during the period of nonrapid eye movement sleep (Seneviratne et al, 2012). Epileptic patients demonstrate multiple sleep abnormalities, including increased sleep latency, fragmented sleep, increased awakenings and stage shifts, and an increase in stages 1 and 2 of nonrapid eye movement sleep (FoldvarySchaefer and Grigg-Damberger, 2009)

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Conclusion