Dravet syndrome (DS) is an epileptic encephalopathy that still lacks biomarkers for epileptogenesis and its treatment. Dysfunction of Na(V)1.1 sodium channels, which are chiefly expressed in... Show moreDravet syndrome (DS) is an epileptic encephalopathy that still lacks biomarkers for epileptogenesis and its treatment. Dysfunction of Na(V)1.1 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 (CBD). Locally disrupting Na(V)1.1 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 (BCs). Our results indicate attenuated theta-gamma coupling as a promising early indicator of inhibitory dysfunction and seizure risk in DS. Show less
