Sleeping on the Job: How studying sleep and circadian rhythm disturbances in a mouse model of Dravet syndrome kept me up at night

Abstract

Epilepsies are among the most common neurological disorders in the world, and sleep disturbances are highly comorbid with many forms of epilepsy. Dravet syndrome (DS) is a severe form of childhood onset epilepsy caused by haploinsufficiency of the Scn1a gene encoding the pore-forming alpha subunit of the NaV1.1 sodium channel, which is expressed primarily in GABAergic neurons. In addition to intractable seizures, DS is characterized by severe sleep disturbances and high risk of sudden death during sleep. Previous characterizations of a mouse model of DS containing a heterozygous deletion of Scn1a demonstrated that these mice display deficits in the circadian regulation of locomotor activity. We predicted that DS mice would also display impaired circadian regulation of sleep and hypothesized that these disturbances are caused by loss of neuronal excitability resulting from reduced NaV1.1 expression in the suprachiasmatic nucleus (SCN), the master circadian clock. Through a combination of genetic, physiological and behavioral experiments, we provide novel insights into the role of NaV1.1 sodium channel expression in the SCN in circadian sleep regulation and the nature of sleep disturbances in this debilitating disease. In addition, we leverage our data to develop novel methods for the analysis of sleep data and encourage more researchers to study the circadian regulation of sleep in pre-clinical models of disease.