KATP channel mutation disrupts hippocampal network activity and nocturnal γ shifts

ATP-sensitive potassium (KATP) channels enable ATP to control the membrane potential and insulin secretion. Humans affected by severe activating mutations in KATP channels suffer from developmental delay, epilepsy and neonatal diabetes (DEND syndrome). While the diabetes in DEND syndrome is well understood, the pathophysiology of the neurological symptoms remains unclear. We hypothesized that parvalbumin-positive interneurons (PV-INs) are key for the pathophysiology and found, by using electrophysiology, that expressing the DEND mutation Kir6.2-V59M selectively in PV-INs reduced intrinsic gamma frequency preference and short-term depression as well as disturbed cognition-associated gamma oscillations and hippocampal sharp waves. Furthermore, risk of seizures is increased and day-night shift in gamma activity disrupted. Thus, PV-INs play a key role in DEND syndrome and this provides a framework for establishing treatment options. One Sentence SummaryOveractive KATP channels in PV-interneurons disturb cellular behaviour and cognition-associated network oscillations.