Molecular mechanism of circadian rhythmicity of seizures in temporal lobe epilepsy

The circadian pattern of seizures in people with epilepsy (PWE) was first described two millennia ago. However, these phenomena have not received enough scientific attention, possibly due to the lack of promising hypotheses to address the interaction between seizure generation and a physiological clock. To propose testable hypotheses at the molecular level, interactions between circadian rhythm, especially transcription factors governing clock genes expression, and the mTOR (mammalian target of rapamycin) signaling pathway, the major signaling pathway in epilepsy, will be reviewed. Then, two closely related hypotheses will be proposed: (1) Rhythmic activity of hyperactivated mTOR signaling molecules results in rhythmic increases in neuronal excitability. These rhythmic increases in excitability periodically exceed the seizure threshold, displaying the behavioral seizures. (2) Oscillation of neuronal excitability in SCN modulates the rhythmic excitability in the hippocampus through subiculum via long-range projections. Findings from published results, their implications, and proposals for new experiments will be discussed. These attempts may ignite further discussion on what we still need to learn about the rhythmicity of spontaneous seizures.