Human mutations in KCNT1, the gene for the Slack Na+-activated K+ channel result in several different childhood epilepsies, including Malignant Migrating Partial Seizures in Infancy (MMPSI) and Autosomal Dominant Frontal Lobe Epilepsy (ADNLFE). These mutations are gain-of-function mutations that result in enhanced channel opening. Although the seizures may abate with adulthood, all disease-causing Slack mutations are associated with very severe intellectual disability. The intellectual deficits may result from the fact that the large intracellular C-terminus of Slack channels interacts with several cytoplasmic signaling molecules, including Phartr-1, Fragile-X Mental Retardation protein (FMRP) and Cytoplasmic FMRP-Interacting Protein (CYFIP1). The two latter proteins are well known regulators of mRNA translation in neurons. We will record from cortical neurons in cultures and in brain slices from mice expressing the human mutation R455H Slack, to determine how the firing patterns of neurons are altered to produce increased excitability, interictal spikes and spontaneous seizures. We will test the actions of a novel inhibitor of Slack channels to determine whether it reverses the effects of the mutation on neuronal firing and seizures and as well as altered patterns of behavior in the R455H mutant animals. Finally we will determine whether the interactions of Slack channels with their cytoplasmic signaling partners are disrupted in the mutant animals, and whether the ability of activation of Slack channels to modulate mRNA translation in neurons is compromised. This work will provide a biological basis for treatment of these devastating diseases and provide potential lead compounds for therapeutic intervention.
Recent evidence has shown that human mutations in the Slack potassium channel lead to early onset epileptic seizures coupled with severe intellectual impairment. The experiments in this proposal will determine how such mutations alter the firing patterns of neurons and the way it interacts with cytoplasmic proteins that regulate protein synthesis in neurons. It also provides a novel therapeutic approach to counteract the effects of mutations that produce these childhood diseases.
