Circadian Genes May Impact Pathogenesis of Pediatric Focal Epilepsy

These functional analyses suggest that the circadian pathway may be a promising target for therapeutic intervention.

PHILADELPHIA — A significant reduction in circadian locomotor output cycles kaput expression results in dysfunction of brain circuits in pediatric patients with focal epilepsy, according to research presented at the 2015 American Epilepsy Society Annual Meeting in Philadelphia.

Judy Liu, MD, PhD, of the Children’s National Medical Center, Washington DC, and fellow researchers enrolled pediatric patients based on their referral for therapeutic surgical resection for focal epilepsy. Researchers used high-resolution 3T magnetic resonance imaging to determine epileptogenic foci and collected samples directly from the operating room for transcriptome analysis.

A mice study was also conducted for histological and gene expression analyses, whole cell patch-clamp electrophysiology, and pentylenetetrazole (PTZ) seizure induction.

Research indicated that compared with normal brain tissue, there was a significant reduction of circadian locomotor output cycles kaput (Clock) expression in epileptogenic tissue. Specifically, 20 out of 25 patients demonstrated decreased Clock.

Among patients with decreased Clock, there were several types of focal cortical dysplasias, tuberous sclerosis complex, Sturge-Weber syndrome, and Rasmussen’s encephalitis, according to Dr. Liu and colleagues.

In the mice study, deletion of Clock in excitatory neurons was associated with loss of spines in the apical dendrite and primary branches, a phenotype the researchers also witnessed in epileptogenic tissue of human pyramidal neurons.

“We demonstrate that mouse excitatory neurons lacking Clock have an imbalance in excitation vs inhibition due to a severe defect in spontaneous [inhibitory postsynaptic currents] as compared with [excitatory postsynaptic currents] ascertained by whole cell patch-clamp electrophysiology,” Dr. Liu and colleagues wrote in the abstract. “This imbalance is associated with a selective reduction of inhibitory synaptic proteins and a reduction in seizure threshold.”

The researchers concluded that circadian genes play a key role in the pathogenesis of pediatric focal epilepsy.

“This study provides a link between the sleep-wake cycle and seizure threshold,” they added. “Furthermore, these functional analyses suggest that the circadian pathway may be a promising target for therapeutic intervention.”

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  1. Liu J, Fu X, Li P, et al. Abstract 3.019|A.01. Loss of Clock results in dysfunction of brain circuits that underlie pediatric focal epilepsy. Presented at: American Epilepsy Society Annual Meeting; Dec. 4-8, 2015; Philadelphia.