Acute effect of antiseizure drugs on background oscillations inScn1aA1783VDravet syndrome mouse model

Abstract

AbstractObjectiveDravet syndrome (Dravet) is a rare and severe form of developmental epileptic encephalopathy. First-line treatment for DS patients includes valproic acid (VA) or clobazam with or without stiripentol (CLB+STP), while sodium channel blockers like carbamazepine (CBZ) or lamotrigine (LTG) are contraindicated. As patients are rarely seizure-free, drug therapy focuses on reducing the seizure burden, as reported by caregivers. In addition to their effect on epileptic phenotypes, antiseizure medications (ASMs) were shown to modify the properties of background neuronal activity. Nevertheless, little is known about these background properties alternations in Dravet.MethodsUtilizing Dravet mice (DS,Scn1aA1783V/WT), we tested the acute effect of several ASMs on background electrocorticography (ECoG) activity and frequency of interictal spikes.ResultsCompared to wild-type mice, background ECoG activity in DS had lower power and reduced phase coherence, which was not corrected by any of the tested ASMs. However, acute administration of Dravet-recommended drugs, including VA or a combination of CLB+STP, caused, in most mice, a reduction of frequency of interictal spikes, alongside an increase in the relative contribution of the beta frequency band. Conversely, CBZ and LTG increased the frequency of interictal spikes with no effect on background spectral properties. Moreover, we uncovered a correlation between the reduction in interictal spike frequency, the drug-induced effect on the power of background activity, and a spectral shift toward higher frequency bands.SignificanceThese data provide a comprehensive analysis of the effect of selected ASMs on the properties of background neuronal oscillations and highlight a possible correlation between their effect on epilepsy and background activity. Thus, examining these properties, following an acute administration, may be used as an additional tool for rapid evaluation of the therapeutic potential of ASMs.Key PointsReduced background power and phase coherence in Dravet miceDS-recommended medicines (VA, CLB+STP) increase the relative beta powerDS-contraindicated drugs (CBZ, LTG) do not cause spectral changesCorrelation between reduction in background power and interictal spike frequencyCorrelation between theta to beta bands ratio and interictal spike frequency