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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.

Figure 1. Schematic diagram of AAV injection and the expression of mCherry encoded by an AAV carrying mCherry in DG neurons.

This study is aimed to explore the molecular mechanism of the core clock gene Bmal1 in the epileptogenesis and seizures of temporal lobe epilepsy (TLE). The authors investigated the expression and distribution of Bmal1 in the hippocampus of TLE and tested the effects of Bmal1 conditional KO (cKO) in hippocampal neurons of Bmal1flox/flox mice on epileptogenesis and seizures. The results suggest that decreased expression of clock gene Bmal1 may participate in the epileptogenesis and seizures via PCDH19 in TLE.
 
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