Decreased expression of the clock gene Bmal1 is involved in the pathogenesis of temporal lobe epilepsy

Abstract

Clock genes not only regulate the circadian rhythm of physiological activities but also participate in the pathogenesis of many diseases. Previous studies have documented the abnormal expression of clock genes in epilepsy. However, the molecular mechanism of brain and muscle Arnt-like protein 1 (Bmal1), one of the core clock genes, in the epileptogenesis and seizures of temporal lobe epilepsy (TLE) remain unclear. We first investigated the levels of Bmal1 and other clock proteins in the hippocampus of subjects with epilepsy to define the function of Bmal1. The levels of Bmal1 were decreased during the latent and chronic phases in the experimental group compared with those in the control group. Knockout of Bmal1 in hippocampal dentate gyrus (DG) neurons of Bmal1flox/flox mice by Synapsin 1 (Syn1) promoter AAV (adeno-associated virus) lowered the threshold of seizures induced by pilocarpine administration. High-throughput sequencing analysis showed that PCDH19 (protocadherin 19), a gene associated with epilepsy, was regulated by Bmal1. PCDH19 expression was also decreased in the hippocampus of epileptic mice. Furthermore, the higher levels of Bmal1 and PCDH19 were detected in patients with no hippocampal sclerosis (no HS) than in patients with HS International League Against Epilepsy (ILAE) type I and III. Altogether, these data suggest that decreased expression of clock gene Bmal1 may participate in epileptogenesis and seizures via PCDH19 in TLE.

Perturbation of Cortical Excitability in a Conditional Model of PCDH19 Disorder

“…Our data support the idea that PCDH19 plays a role in synapse and circuit maintenance throughout life, since mice injected with Cre-AAV as adults displayed a phenotype, both in terms of hyperexcitability and SWA disruption. This data is consistent with the recent finding that reduced expression of the clock gene BMAL1 in adult mice causes a loss of PCDH19 expression and an increase in susceptibility to epilepsy [ 42 ]. These findings have important implications for patients since some of the symptoms are caused by the role of PCDH19 in the mature brain and could possibly be reversed by correcting gene function later in life.…”

Perturbation of cortical excitability in a conditional model of PCDH19 disorder

“…Our data support the idea that PCDH19 plays a role in synapse and circuit maintenance throughout life, since mice injected with Cre-AAV as adults displayed a phenotype, both in terms of hyperexcitability and SWA disruption. This data is consistent with the recent finding that reduced expression of the clock gene BMAL1 in adult mice causes a loss of PCDH19 expression and an increase in susceptibility to epilepsy 42 . These findings have important implications for patients as it means that at least some of the symptoms are caused by the role of PCDH19 in the mature brain and could possibly be reversed by correcting gene function later in life.…”

Circadian regulation of dentate gyrus excitability mediated by G-protein signaling

“…Short, high frequency bursts of GCs spikes have been reported in active GCs in vivo, and there is increased propensity for this form of bursting in GCs from epileptic tissue (Kelly and Beck, 2017;Pernia-Andrade and Jonas, 2014). Considering the established role of the DG as the hippocampal gate for seizure propagation and recent evidence that disruption of circadian transcriptional loops modify seizure thresholds (Wu et al, 2021;Zhang et al, 2021), our findings present a promising inroad to address a chronotherapeutic approach in the management of TLE (Karoly et al, 2021). (B) Violin plots showing effects of CGP55845 (red) or ML297 (green) during the Light and Dark phases.…”

“…While diurnal rhythms of synaptic function related to sleep-wake cycles are well-established (Bridi et al, 2020; Liu et al, 2010; Vyazovskiy et al, 2008), it is unclear whether local transcriptional clocks in the hippocampus also affect membrane excitability. Addressing this question is important for understanding how disruption of clock components contribute to abnormal excitability and epilepsy, as well as the daily rhythms of normal behavior (Debski et al, 2020; Snider et al, 2018; Wu et al, 2021; Zhang et al, 2021).…”