Acute effect of antiseizure drugs on background oscillations in Scn1aA1783V Dravet syndrome mouse model

Abstract

Dravet syndrome (Dravet) is a rare and severe form of developmental epileptic encephalopathy. Antiseizure medications (ASMs) for Dravet patients include valproic acid (VA) or clobazam (CLB), with or without stiripentol (STP), while sodium channel blockers like carbamazepine (CBZ) or lamotrigine (LTG) are contraindicated. In addition to their effect on epileptic phenotypes, ASMs were shown to modify the properties of background neuronal activity. Nevertheless, little is known about these background properties alterations in Dravet. Here, utilizing Dravet mice (DS, Scn1aA1783V/WT), we tested the acute effect of several ASMs on background electrocorticography (ECoG) activity and frequency of interictal spikes. Compared to wild-type mice, background ECoG activity in DS mice had lower power and reduced phase coherence, which was not corrected by any of the tested ASMs. However, acute administration of Dravet-recommended drugs, VA, CLB, or a combination of CLB + STP, caused, in most mice, a reduction in the 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. Together, these 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.

Contraindicated Drug Responses in Dravet Syndrome Brain Organoids Utilizing Micro Electrode Array Assessment Methods

“…In the CMOS-MEA measurements conducted after CBZ administration, the outcomes revealed an augmentation in activities beyond oscillatory behaviors [Figure 2(Bb)]. Notably, in the ECoG of the DS mouse model, an escalation in spike activities outside of seizure events following CBZ administration has been documented [58]. The response witnessed in our study may potentially mirror the response observed in mouse models, implying a degree of coherence between the findings in our study and the responses seen in the mouse model.…”

Therapeutic effects of KRM-II-81, positive allosteric modulator for α2/3 subunit containing GABAA receptors, in a mouse model of Dravet syndrome

“…In the mice model of DS, the decreased excitability of fast-spiking interneuron (Yu et al, 2006;Ogiwara et al, 2007) and reduced frequency of spontaneous inhibitory post-synaptic currents in pyramidal neurons (Han et al, 2012;Beretta et al, 2022)has been illustrated as a pathophysiology of DS. This insight is supported by clinical and experimental knowledge that epileptic features can be aggravated by anti-seizure drugs which blocks sodium channel blockers (Wirrell et al, 2022;Quinn et al, 2023). The precise mechanisms underlying the symptoms of DS might be more complex because recent studies provide the evidence that the electrophysiological properties of DS models can be altered depending on age or stage of symptomatic severity (Favero et al, 2018;Almog et al, 2021).…”

“…Because the impairment of fast spiking interneuron firing is regarded as one of the pathophysiological mechanisms of DS, an augmentation of GABA A receptor-mediated inhibition would be the potential therapeutic strategies. Clobazam, one of the benzodiazepine class medications, is often used to treat epilepsy in patients with DS ( Wirrell et al, 2022 ), and its efficacy has been shown in DS model mice ( Hawkins et al, 2017 ; Quinn et al, 2023 ). GABA A receptors are assembled from multiple subunit gene products and form mostly hetero-oligomeric pentamers ( Olsen and Sieghart, 2008 ).…”