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.