Impaired theta-gamma coupling indicates inhibitory dysfunction and seizure risk in a Dravet syndrome mouse model.

Dravet syndrome (DS) is an epileptic encephalopathy that still lacks biomarkers for epileptogenesis and its treatment. Dysfunction of NaV1.1 sodium channels, which are chiefly expressed in inhibitory interneurons, explains the epileptic phenotype. Understanding the network effects of these cellular deficits may help predict epileptogenesis. Here, we studied theta-gamma coupling as a potential marker for altered inhibitory functioning and epileptogenesis in a DS mouse model. We found that cortical theta-gamma coupling was reduced in both male and female juvenile DS mice and persisted only if spontaneous seizures occurred. Theta-gamma coupling was partly restored by cannabidiol. Locally disrupting NaV1.1 expression in the hippocampus or cortex yielded early attenuation of theta-gamma coupling, which in the hippocampus associated with fast ripples, and which was replicated in a computational model when voltage-gated sodium currents were impaired in basket cells. Our results indicate attenuated theta-gamma coupling as a promising early indicator of inhibitory dysfunction and seizure risk in DS.SIGNIFICANCE STATEMENTBiomarkers for Dravet syndrome (DS), a severe type of childhood epilepsy, are currently not available. Despite advances in our understanding of the cellular pathophysiology of DS, the effects on brain network dynamics largely remain to be uncovered. In the present work we show that decreased theta-gamma coupling precedes and associates with seizure activity in a DS mouse model, which could be replicated by brain region-specific ablation of NaV1.1, a sodium channel affected in the majority of DS patients. Computational modelling of sodium channel dysfunction in inhibitory interneurons yielded a similar decrease in theta-gamma coupling. Together, these results suggest that impaired theta-gamma coupling is a promising early indicator of inhibitory dysfunction and seizure risk in DS.