Neocortical and Hippocampal Circuit Dysfunction in the KCNT1 Model of Epilepsy

Variants of the KCNT1 gene encoding the Na+ activated K+ channel results in intellectual disability and a range of developmental seizure disorders including epilepsy of infancy with migrating focal seizures and sleep-related hypermotor epilepsy. Prior in vitro electrophysiology in the KCNT1 knock-in variant mouse model showed that hypoexcitability of a non-fast spiking interneuron subtype in the frontal lobe was the likely cause of local seizure induction during Non-REM sleep, and contextual fear learning deficits. The extent to which the KCNT1 variant modifies circuit activity in limbic and frontal regions, and whether these changes result from interneuronopathy of somatostatin (SST+) or parvalbumin positive (PV+) cells, remain fundamental questions in this model. We therefore propose simultaneous high-density electrophysiological characterization and optogenetic testing of activity in dentate gyrus SST+ and PV+ interneuron subtypes. This approach provides unprecedented detail of the relationship between cell and circuit function in control and KCNT1 mice. Preliminary KCNT1 data show hypersynchronous hippocampal IEDs and significantly larger dentate spikes, suggesting alteration of the microcircuitry governing entorhinal-hippocampal pathways. We hypothesize that: A) Hypersynchronous oscillations the KCNT1 hippocampus result from failure of local SST+ interneuron inhibition and loss of regional circuit regulation; and B) Selective stimulation of SST+ interneurons, more so than PV+ interneurons, will rectify inhibitory function and attenuate inter-ictal epileptiform discharges (IEDs). These experiments could establish a necessary causal link between gene-induced interneuronopathy, cell function and circuit susceptibility to hyperexcitation and a novel approach for rescuing inhibitory regulation. We will also study the long-term effects of chronic cell-type selective stimulation on seizure and cognitive outcomes through long-term video and EEG monitoring and performance on the active avoidance behavioral task.