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

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.

Loss of CLOCK Results in Dysfunction of Brain Circuits Underlying Focal Epilepsy

“…Although BMAL1 level is not altered in human FCD tissue, its function may be altered by dysregulation of the mTOR pathway in TSC. BMAL1 may therefore contribute to epileptogenesis, a hypothesis supported by studies showing that its deletion reduces seizure threshold in mice (Gerstner et al, 2014). …”

“…In the FCD cases with decreased CLOCK, we examined other components of the main circadian regulatory loop. BMAL1 gene, which dimerizes with CLOCK and regulates seizure threshold in mice (Gerstner et al, 2014), is unchanged in epileptogenic FCD tissues (Figure 2C). In contrast, we find that Cryptochrome (Cry) and Period (Per) proteins, downstream targets of CLOCK/BMAL1, are significantly decreased (Figure 2C; Figure S2A).…”

“…In the cerebral cortex, its role is not fully understood. Nevertheless, the binding partner of CLOCK, the brain muscle ARNT-like 1 (BMAL1), alters seizure threshold in mice (Gerstner et al, 2014) and also regulates the mTOR pathway (Lipton et al, 2015). Furthermore, epilepsy has a known association with the sleep/wake cycle (Bourgeois, 1996).…”

Mechanisms linking circadian clocks, sleep, and neurodegeneration

“…Bmal1 deficient mice develop striking neurological phenotypes, including profound spontaneous astrogliosis, increased oxidative damage, synaptic degeneration, impaired brain functional connectivity (12), impaired learning and memory (60), altered hippocampal neurogenesis (76–78), and lowered seizure threshold (79). In some of these cases, it remains unclear if the phenotype is due to loss of Bmal1 in the cells of the brain itself, or secondary to whole-animal changes in metabolism.…”

The Diathesis–Epilepsy Model: How Past Events Impact the Development of Epilepsy and Comorbidities

“…Because seizure threshold is also regulated in a circadian manner in a BMAL1-dependent manner (Gerstner et al 2014), one can propose, as a working hypothesis, that normal epigenetic-circadian mechanisms in addition to the modifications brought about by past life experiences and proepileptogenic brain insults, bring neuronal networks close to seizure threshold at specific time points during the night and day cycle. Thus, diathesis is likely regulated across multiple timescales (Fig.…”