Circadian Rhythm Protein CLOCK linked to severe epilepsy

In new research published in Neuron this week researchers from Brown University in Providence, RI suggests that disruption of  the circadian rhythm protein CLOCK alters cortical circuits and may lead to generation of focal epilepsy. 

Dr. Liu and her colleagues used resected brain tissue from epilepsy surgery for focal cortical dyplasias and analysed the  tissue's transcriptome, or a survey of the messenger RNA (mRNA) in any given population of cells. They used adjacent healthy tissue as controls.The researchers were looking at differences between healthy and epileptogenic tissue and to their surprise found that  there was a decrease in the expression of mRNA coding for a protein called circadian locomotor output cycles kaput (CLOCK) in the epileptogenic tissue.

CLOCK is a key player in the regulation of our circadian rhythms. Mice with mutated versions of the gene are unable to maintain normal daily rhythms of sleep and wakefulness. In the unhealthy brain tissue from participants with epilepsy, CLOCK was reduced in both excitatory and inhibitory neuron. CLOCK is important for regulating a range of genes and other CLOCK-associated proteins were also absent or reduced in the brain tissue.

To investigate this further the researchers generated and tested separate knock out mouse models with targeted deletions of the CLOCK gene in excitatory and inhibitory neurons. They found that the mice without CLOCK in their excitatory neurons showed symptoms of epilepsy similar to those in the human patients, including an increased susceptibility to seizures - especially when waking up. 

They also found that excitatory neurons that lacked CLOCK received less inhibitory inputs from surrounding cells, in effect unleashing them and potentially giving them a lower threshold for the onset of seizures. The findings will certainly put more focus on the role of CLOCK in the molecular mechanisms behind epilepsy.