Decreased Clock Gene Bmal1 Mediates Epileptogenesis via PCDH19 in 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 found the abnormal expression of clock genes in epilepsy. However, as the core clock gene, the molecular mechanism of Bmal1 in the epileptogenesis and seizures of temporal lobe epilepsy (TLE) is still unclear. To define the function of Bmal1, we firstly investigated the levels of Bmal1 and other clock proteins in the hippocampus in epilepsy. In the latency and chronic phases, the levels of Bmal1 were decreased compared with 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. And the expression of PCDH19 was also decreased in the hippocampus of epileptic mice. Furthermore, the levels of Bmal1 and PCDH19 were higher in the patients with no hippocampal sclerosis (no HS), compared to HS International League Against Epilepsy (ILAE) type I and III. Altogether, these data suggest that decreased expression of clock gene Bmal1 may participate in the epileptogenesis and seizures via PCDH19 in TLE.