Novel Compensatory Mechanisms Enable the Mutant KCNT1 Channels to Induce Seizures

Abstract

Mutations in the sodium-activated potassium channel (KCNT1) gene are linked to epilepsy. Surprisingly, all KCNT1 mutations examined to date increase K+ current amplitude. These findings present a major neurophysiological paradox: how do gain-of-function KCNT1 mutations expected to silence neurons cause epilepsy? Here, we use Drosophila to show that expressing mutant KCNT1 in GABAergic neurons leads to seizures, consistent with the notion that silencing inhibitory neurons tips the balance towards hyperexcitation. Unexpectedly, mutant KCNT1 expressed in motoneurons also causes seizures. One striking observation is that mutant KCNT1 causes abnormally large and spontaneous EJPs (sEJPs). Our data suggest that these sEJPs result from local depolarization of synaptic terminals due to a reduction in Shaker channel levels and more active Na+ channels. Hence, we provide the first in vivo evidence that both disinhibition of inhibitory neurons and compensatory plasticity in motoneurons can account for the paradoxical effects of gain-of-function mutant KCNT1 in epilepsy.

In silico model reveals the key role of GABA in KCNT1‐epilepsy in infancy with migrating focal seizures

“…This results in a strong increase of the excitation‐to‐inhibition ratio, thereby increasing excitability and synchrony at the network level. One preprint and one recent study seemed to validate the localization of slack in both glutamatergic and GABAergic neurons 47,48 . Predictions of our model seemed in phase with the report of Shore et al showing similar firing curves in the different subtypes of neurons, with a predominant impact on GABAergic neurons (Figure ) 47 …”

“…One preprint and one recent study seemed to validate the localization of slack in both glutamatergic and GABAergic neurons. 47,48 Predictions of our model seemed in phase with the report of Shore et al showing similar firing curves in the different subtypes of neurons, with a predominant impact on GABAergic neurons ( Figure S2). 47 In our study, we moved from a microscopic to a macroscopic model by adapting the wave-to-pulse functions of the different subpopulations according to frequency-intensity curves for each neuronal type.…”

KCNT1 epilepsy with migrating focal seizures shows a temporal sequence with poor outcome, high mortality and SUDEP

“…Finally, patients show severe delay in gross motor function with a severe hypotonia. Since KNCT1 gain of function lead to a disruption of motoneuronal functions in fly model (Ehaideb et al, 2017), we cannot exclude that hypotonia can have a multi-origin, central with the strong expression of KCNT1 in cortex and cerebellar tissue (supplementary Fig.2) with the presence of cerebellar atrophy on MRIs of some of our patients and peripheral with the possible involvement of the neuromuscular junction. Such dual disorders of the CNS and the neuromuscular junction were also reported in Dravet syndrome, another DEE caused by mutations in SCN1A (Gitiaux et al, 2016).…”

“…Epilepsy (ADNFLE) and Ohtahara syndrome (Heron et al, 2012;Martin et al, 2014). To date, around 60 patients associating KCNT1 mutations and EIMFS are reported with variable and often incomplete information on seizures, EEGs, therapies, MRI and neurodevelopmental status (McTague et al, 2018;Ishii et al, 2013;McTague et al, 2013;Bearden et al, 2014, Mikati et al, 2015bMøller et al, 2015;Ohba et al, 2015;Mori et al, 2016;Rizzo et al, 2016;de Kovel et al, 2016;Baumer and Sheehan, 2017;Zhang et al, 2017;Jee N et al, 2017;Kawasaki et al, 2017;Madaan et al, 2017;Abdelnour et al, 2018;Numis et al, 2018;Dilena et al, 2018). Many questions remain unanswered, mainly on the prognosis and the long-term outcome.…”