Allostatic Compensatory Mechanisms Enable the Mutant KCNT1 Channels to Induce Seizures and Hyperexcitability

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 excitatory neurons also causes seizures. Further observations reveal that mutant KCNT1 causes abnormally large and spontaneous excitatory junction potentials (sEJPs), which are shown to be resulting from local depolarization of synaptic terminals due to a reduction in Shaker and Eag channel levels and more active Na and Ca2 channels. Such compensatory changes are likely mediated by the transcriptional factor Islet. Hence, we provide the first in vivo evidence that both disinhibition of inhibitory neurons and allostatic compensatory plasticity in excitatory neurons might account for the paradoxical effects of gain-of-function mutant KCNT1 in epilepsy.