Impaired θ-γ Coupling Indicates Inhibitory Dysfunction and Seizure Risk in a Dravet Syndrome Mouse Model

Abstract

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 inhibitory interneurons, explains the epileptic phenotype. Understanding the network effects of these cellular deficits may help predict epileptogenesis. Here, we studied h-c coupling as a potential marker for altered inhibitory functioning and epileptogenesis in a DS mouse model. We found that cortical h-c coupling was reduced in both male and female juvenile DS mice and persisted only if spontaneous seizures occurred. h-c Coupling was partly restored by cannabidiol (CBD). Locally disrupting Na V 1.1 expression in the hippocampus or cortex yielded early attenuation of h-c 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 h-c coupling as a promising early indicator of inhibitory dysfunction and seizure risk in DS.

Channelopathy of Dravet Syndrome and Potential Neuroprotective Effects of Cannabidiol

“…105 Intriguingly, θ-γ coupling may serve as an early indicator of inhibitory dysfunction and seizure risk in DS and θ-γ coupling reduction in DS mice model was partly restored by CBD. 106 Another interesting example is the finding that overexpression of beta-amyloid peptide, the pathogenic amyloid-forming fragment in Alzheimer disease (AD), drives down SCN1A expression in cortical interneurons. 107 This secondary SCN1A lesion may contribute in part to the hyperexcitability identified in both mouse models and patients with AD dementia.…”

Deciphering in silico the Role of Mutated NaV1.1 Sodium Channels in Enhancing Trigeminal Nociception in Familial Hemiplegic Migraine Type 3

“…In our modeling approach, we did not simulate the outcome of changes in Na V 1.1 in central neurons where these channels are expressed in interneurons (Favero et al, 2018;Sakkaki et al, 2020). Recently, computer modeling of various neuron types, similar to our whole nerve paradigm, was used to predict functional outcome of an FHM3 mutation on the central neuronal network of transgenic Dravet mice, in which Na V 1.1 channels were ablated in hippocampus and cortex (Jansen et al, 2020b). One could model the role of Na V 1.1 channels in CSD events associated with FHM3 or analogous PID in stroke to assess brain recovery after ischemia (Sukhotinsky et al, 2010).…”

Bad Timing for Epileptic Networks: Role of Temporal Dynamics in Seizures and Cognitive Deficits

“…25,26 In animal models of DS carrying Scn1a mutations, hippocampal SPW-R frequency and their associated HFOs are reduced and the modulation of g oscillations by q rhythm is altered. 27,28 The fact that brain rhythms are abnormal in epilepsy and that such alteration is correlated with cognitive performance deficits does not necessarily mean causation. Indeed, both alterations of oscillations and cognitive deficits occur in the context of seizure activity, and seizures could be the main driver of cognitive deficits.…”

“… 25 , 26 In animal models of DS carrying Scn1a mutations, hippocampal SPW-R frequency and their associated HFOs are reduced and the modulation of γ oscillations by θ rhythm is altered. 27 , 28 …”