KATPchannel mutation disrupts hippocampal network activity and nocturnal γ shifts

ATP-sensitive potassium (K ATP ) channels enable ATP to control the membrane potential and insulin secretion. Humans affected by severe activating mutations in K ATP channels suffer from developmental d elay, e pilepsy and n eonatal d iabetes (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 K ir 6.2-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 Summary Overactive K ATP channels in PV-interneurons disturb cellular behaviour and cognition-associated network oscillations.